Full text data of ACTN1
ACTN1
[Confidence: low (only semi-automatic identification from reviews)]
Alpha-actinin-1 (Alpha-actinin cytoskeletal isoform; F-actin cross-linking protein; Non-muscle alpha-actinin-1)
Alpha-actinin-1 (Alpha-actinin cytoskeletal isoform; F-actin cross-linking protein; Non-muscle alpha-actinin-1)
UniProt
P12814
ID ACTN1_HUMAN Reviewed; 892 AA.
AC P12814; B3V8S3; B4DHH3; B7TY16; Q1HE25; Q9BTN1;
DT 01-OCT-1989, integrated into UniProtKB/Swiss-Prot.
read moreDT 13-APR-2004, sequence version 2.
DT 22-JAN-2014, entry version 172.
DE RecName: Full=Alpha-actinin-1;
DE AltName: Full=Alpha-actinin cytoskeletal isoform;
DE AltName: Full=F-actin cross-linking protein;
DE AltName: Full=Non-muscle alpha-actinin-1;
GN Name=ACTN1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Placenta;
RX PubMed=2780298; DOI=10.1093/nar/17.16.6725;
RA Millake D.B., Blanchard A.D., Patel B., Critchley D.R.;
RT "The cDNA sequence of a human placental alpha-actinin.";
RL Nucleic Acids Res. 17:6725-6725(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=2349951;
RA Youssoufian H., McAfee M., Kwiatkowski D.J.;
RT "Cloning and chromosomal localization of the human cytoskeletal alpha-
RT actinin gene reveals linkage to the beta-spectrin gene.";
RL Am. J. Hum. Genet. 47:62-71(1990).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RX PubMed=18353764; DOI=10.1074/mcp.M700590-MCP200;
RA Thorsen K., Sorensen K.D., Brems-Eskildsen A.S., Modin C.,
RA Gaustadnes M., Hein A.M., Kruhoffer M., Laurberg S., Borre M.,
RA Wang K., Brunak S., Krainer A.R., Torring N., Dyrskjot L.,
RA Andersen C.L., Orntoft T.F.;
RT "Alternative splicing in colon, bladder, and prostate cancer
RT identified by exon array analysis.";
RL Mol. Cell. Proteomics 7:1214-1224(2008).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
RC TISSUE=Tongue;
RA Mancini U.M., Tajara E.H.;
RT "A new mRNA isoform from ACTN1 gene.";
RL Submitted (APR-2006) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4).
RA Mansilla F., Orntoft T.F., Birkenkamp-Demtroeder K.;
RT "Actinin alpha 1 alternative splicing variant.";
RL Submitted (OCT-2008) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Brain;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12508121; DOI=10.1038/nature01348;
RA Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C.,
RA Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A.,
RA Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S.,
RA Sun H., Du H., Pepin K., Artiguenave F., Robert C., Cruaud C.,
RA Bruels T., Jaillon O., Friedlander L., Samson G., Brottier P.,
RA Cure S., Segurens B., Aniere F., Samain S., Crespeau H., Abbasi N.,
RA Aiach N., Boscus D., Dickhoff R., Dors M., Dubois I., Friedman C.,
RA Gouyvenoux M., James R., Madan A., Mairey-Estrada B., Mangenot S.,
RA Martins N., Menard M., Oztas S., Ratcliffe A., Shaffer T., Trask B.,
RA Vacherie B., Bellemere C., Belser C., Besnard-Gonnet M.,
RA Bartol-Mavel D., Boutard M., Briez-Silla S., Combette S.,
RA Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C., Muselet D.,
RA Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P., Trybou A.,
RA Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M.,
RA Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V.,
RA Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L.,
RA Verdier J., Verdier-Discala C., Hillier L.W., Fulton L., McPherson J.,
RA Matsuda F., Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W.,
RA Quetier F., Waterston R., Hood L., Weissenbach J.;
RT "The DNA sequence and analysis of human chromosome 14.";
RL Nature 421:601-607(2003).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Colon, and Skin;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [11]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 297-892 (ISOFORM 1).
RX PubMed=2169343;
RA Nishiyama M., Ozturk M., Frohlich M., Mafune K., Steele G. Jr.,
RA Wands J.R.;
RT "Expression of human alpha-actinin in human hepatocellular
RT carcinoma.";
RL Cancer Res. 50:6291-6294(1990).
RN [12]
RP PROTEIN SEQUENCE OF 1-21.
RC TISSUE=Platelet;
RX PubMed=12665801; DOI=10.1038/nbt810;
RA Gevaert K., Goethals M., Martens L., Van Damme J., Staes A.,
RA Thomas G.R., Vandekerckhove J.;
RT "Exploring proteomes and analyzing protein processing by mass
RT spectrometric identification of sorted N-terminal peptides.";
RL Nat. Biotechnol. 21:566-569(2003).
RN [13]
RP PROTEIN SEQUENCE OF 134-146.
RX PubMed=8713105; DOI=10.1006/bbrc.1996.1082;
RA Egerton M., Moritz R.L., Druker B., Kelso A., Simpson R.J.;
RT "Identification of the 70kD heat shock cognate protein (Hsc70) and
RT alpha-actinin-1 as novel phosphotyrosine-containing proteins in T
RT lymphocytes.";
RL Biochem. Biophys. Res. Commun. 224:666-674(1996).
RN [14]
RP PROTEIN SEQUENCE OF 566-577; 727-738 AND 835-863, AND SUBCELLULAR
RP LOCATION.
RX PubMed=7750553; DOI=10.1016/0014-5793(95)00362-D;
RA Dubernard V., Faucher D., Launay J.-M., Legrand C.;
RT "Identification of the cytoskeletal protein alpha-actinin as a
RT platelet thrombospondin-binding protein.";
RL FEBS Lett. 364:109-114(1995).
RN [15]
RP INTERACTION WITH TTID.
RX PubMed=10369880; DOI=10.1093/hmg/8.7.1329;
RA Salmikangas P., Mykkaenen O.M., Groenholm M., Heiska L., Kere J.,
RA Carpen O.;
RT "Myotilin, a novel sarcomeric protein with two Ig-like domains, is
RT encoded by a candidate gene for limb-girdle muscular dystrophy.";
RL Hum. Mol. Genet. 8:1329-1336(1999).
RN [16]
RP INTERACTION WITH MYOZ2.
RX PubMed=11114196; DOI=10.1073/pnas.260501097;
RA Frey N., Richardson J.A., Olson E.N.;
RT "Calsarcins, a novel family of sarcomeric calcineurin-binding
RT proteins.";
RL Proc. Natl. Acad. Sci. U.S.A. 97:14632-14637(2000).
RN [17]
RP PHOSPHORYLATION AT TYR-12.
RX PubMed=11369769; DOI=10.1074/jbc.M101678200;
RA Izaguirre G., Aguirre L., Hu Y.P., Lee H.Y., Schlaepfer D.D.,
RA Aneskievich B.J., Haimovich B.;
RT "The cytoskeletal/non-muscle isoform of alpha-actinin is
RT phosphorylated on its actin-binding domain by the focal adhesion
RT kinase.";
RL J. Biol. Chem. 276:28676-28685(2001).
RN [18]
RP INTERACTION WITH LPP.
RX PubMed=12615977; DOI=10.1242/jcs.00309;
RA Li B., Zhuang L., Reinhard M., Trueb B.;
RT "The lipoma preferred partner LPP interacts with alpha-actinin.";
RL J. Cell Sci. 116:1359-1366(2003).
RN [19]
RP INTERACTION WITH DDN.
RX PubMed=16464232; DOI=10.1111/j.1471-4159.2006.03679.x;
RA Kremerskothen J., Kindler S., Finger I., Veltel S., Barnekow A.;
RT "Postsynaptic recruitment of Dendrin depends on both dendritic mRNA
RT transport and synaptic anchoring.";
RL J. Neurochem. 96:1659-1666(2006).
RN [20]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-95; LYS-195 AND LYS-676, AND
RP MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [21]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [22]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, PHOSPHORYLATION [LARGE
RP SCALE ANALYSIS] AT SER-6, AND MASS SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [23]
RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 30-253.
RX PubMed=16698282; DOI=10.1016/j.jsb.2006.01.013;
RA Borrego-Diaz E., Kerff F., Lee S.H., Ferron F., Li Y., Dominguez R.;
RT "Crystal structure of the actin-binding domain of alpha-actinin 1:
RT evaluating two competing actin-binding models.";
RL J. Struct. Biol. 155:230-238(2006).
RN [24]
RP VARIANTS BDPLT15 LYS-32; GLN-46; ILE-105; LYS-225; TRP-738 AND
RP GLN-752, VARIANT TRP-197, AND CHARACTERIZATION OF VARIANTS BDPLT15
RP LYS-32 AND ILE-105.
RX PubMed=23434115; DOI=10.1016/j.ajhg.2013.01.015;
RA Kunishima S., Okuno Y., Yoshida K., Shiraishi Y., Sanada M.,
RA Muramatsu H., Chiba K., Tanaka H., Miyazaki K., Sakai M., Ohtake M.,
RA Kobayashi R., Iguchi A., Niimi G., Otsu M., Takahashi Y., Miyano S.,
RA Saito H., Kojima S., Ogawa S.;
RT "ACTN1 mutations cause congenital macrothrombocytopenia.";
RL Am. J. Hum. Genet. 92:431-438(2013).
CC -!- FUNCTION: F-actin cross-linking protein which is thought to anchor
CC actin to a variety of intracellular structures. This is a bundling
CC protein.
CC -!- SUBUNIT: Homodimer; antiparallel. Interacts with DDN, MYOZ2,
CC PDLIM2, TTID and LPP. Interacts with PSD. Interacts with MICALL2
CC (By similarity).
CC -!- INTERACTION:
CC P12931:SRC; NbExp=2; IntAct=EBI-351710, EBI-621482;
CC Q8VC66:Ssx2ip (xeno); NbExp=3; IntAct=EBI-351710, EBI-6654049;
CC Q8WZ42:TTN; NbExp=2; IntAct=EBI-351710, EBI-681210;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton. Cytoplasm,
CC myofibril, sarcomere, Z line. Cell membrane (By similarity). Cell
CC junction (By similarity). Cell projection, ruffle (By similarity).
CC Note=Colocalizes with MYOZ2 and PPP3CA at the Z-line of heart and
CC skeletal muscle. Colocalizes with PSD in membrane ruffles and
CC central reticular structures (By similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1;
CC IsoId=P12814-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P12814-2; Sequence=VSP_041264;
CC Name=3;
CC IsoId=P12814-3; Sequence=VSP_043525;
CC Name=4;
CC IsoId=P12814-4; Sequence=VSP_041264, VSP_047763;
CC -!- DISEASE: Bleeding disorder, platelet-type 15 (BDPLT15)
CC [MIM:615193]: An autosomal dominant form of macrothrombocytopenia.
CC Affected individuals usually have no or only mild bleeding
CC tendency, such as epistaxis. Laboratory studies show decreased
CC numbers of large platelets and anisocytosis, but the platelets
CC show no in vitro functional abnormalities. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the alpha-actinin family.
CC -!- SIMILARITY: Contains 1 actin-binding domain.
CC -!- SIMILARITY: Contains 2 CH (calponin-homology) domains.
CC -!- SIMILARITY: Contains 2 EF-hand domains.
CC -!- SIMILARITY: Contains 4 spectrin repeats.
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DR EMBL; X15804; CAA33803.1; -; mRNA.
DR EMBL; M95178; AAA51582.1; -; mRNA.
DR EMBL; EU716325; ACE62922.1; -; mRNA.
DR EMBL; DQ496098; ABF50047.1; -; mRNA.
DR EMBL; FJ410030; ACJ24535.1; -; mRNA.
DR EMBL; BT007207; AAP35871.1; -; mRNA.
DR EMBL; AK295099; BAG58135.1; -; mRNA.
DR EMBL; AL117694; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471061; EAW80975.1; -; Genomic_DNA.
DR EMBL; BC003576; AAH03576.1; -; mRNA.
DR EMBL; BC015766; AAH15766.1; -; mRNA.
DR EMBL; X55187; CAA38970.1; -; mRNA.
DR PIR; S05503; FAHUAA.
DR RefSeq; NP_001093.1; NM_001102.3.
DR RefSeq; NP_001123476.1; NM_001130004.1.
DR RefSeq; NP_001123477.1; NM_001130005.1.
DR RefSeq; XP_005268207.1; XM_005268150.1.
DR UniGene; Hs.509765; -.
DR PDB; 2EYI; X-ray; 1.70 A; A=30-253.
DR PDB; 2EYN; X-ray; 1.80 A; A=30-253.
DR PDBsum; 2EYI; -.
DR PDBsum; 2EYN; -.
DR ProteinModelPortal; P12814; -.
DR SMR; P12814; 30-254, 267-892.
DR DIP; DIP-33184N; -.
DR IntAct; P12814; 36.
DR MINT; MINT-215335; -.
DR STRING; 9606.ENSP00000377941; -.
DR PhosphoSite; P12814; -.
DR DMDM; 46397817; -.
DR OGP; P12814; -.
DR PaxDb; P12814; -.
DR PeptideAtlas; P12814; -.
DR PRIDE; P12814; -.
DR DNASU; 87; -.
DR Ensembl; ENST00000193403; ENSP00000193403; ENSG00000072110.
DR Ensembl; ENST00000394419; ENSP00000377941; ENSG00000072110.
DR Ensembl; ENST00000438964; ENSP00000414272; ENSG00000072110.
DR Ensembl; ENST00000538545; ENSP00000439828; ENSG00000072110.
DR GeneID; 87; -.
DR KEGG; hsa:87; -.
DR UCSC; uc001xkk.3; human.
DR CTD; 87; -.
DR GeneCards; GC14M069341; -.
DR HGNC; HGNC:163; ACTN1.
DR HPA; CAB004303; -.
DR HPA; HPA006035; -.
DR MIM; 102575; gene.
DR MIM; 615193; phenotype.
DR neXtProt; NX_P12814; -.
DR Orphanet; 140957; Autosomal dominant macrothrombocytopenia.
DR PharmGKB; PA24; -.
DR eggNOG; COG5069; -.
DR HOGENOM; HOG000263418; -.
DR HOVERGEN; HBG050453; -.
DR KO; K05699; -.
DR OMA; WIRRTMP; -.
DR OrthoDB; EOG72C4ZJ; -.
DR Reactome; REACT_111155; Cell-Cell communication.
DR Reactome; REACT_118779; Extracellular matrix organization.
DR Reactome; REACT_604; Hemostasis.
DR ChiTaRS; ACTN1; human.
DR EvolutionaryTrace; P12814; -.
DR GeneWiki; Actinin,_alpha_1; -.
DR GenomeRNAi; 87; -.
DR NextBio; 323; -.
DR PRO; PR:P12814; -.
DR ArrayExpress; P12814; -.
DR Bgee; P12814; -.
DR CleanEx; HS_ACTN1; -.
DR Genevestigator; P12814; -.
DR GO; GO:0005856; C:cytoskeleton; IEA:UniProtKB-SubCell.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0043197; C:dendritic spine; IEA:Ensembl.
DR GO; GO:0070062; C:extracellular vesicular exosome; IDA:UniProtKB.
DR GO; GO:0005916; C:fascia adherens; IEA:Ensembl.
DR GO; GO:0005925; C:focal adhesion; IMP:UniProtKB.
DR GO; GO:0005634; C:nucleus; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0031093; C:platelet alpha granule lumen; TAS:Reactome.
DR GO; GO:0031143; C:pseudopodium; TAS:UniProtKB.
DR GO; GO:0001726; C:ruffle; IEA:UniProtKB-SubCell.
DR GO; GO:0030018; C:Z disc; IEA:UniProtKB-SubCell.
DR GO; GO:0005509; F:calcium ion binding; IEA:InterPro.
DR GO; GO:0003725; F:double-stranded RNA binding; IDA:MGI.
DR GO; GO:0005178; F:integrin binding; IDA:UniProtKB.
DR GO; GO:0051017; P:actin filament bundle assembly; IEA:Ensembl.
DR GO; GO:0030198; P:extracellular matrix organization; TAS:Reactome.
DR GO; GO:0048041; P:focal adhesion assembly; IMP:UniProtKB.
DR GO; GO:0051271; P:negative regulation of cellular component movement; IMP:UniProtKB.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0002576; P:platelet degranulation; TAS:Reactome.
DR GO; GO:0042981; P:regulation of apoptotic process; NAS:UniProtKB.
DR Gene3D; 1.10.238.10; -; 2.
DR Gene3D; 1.10.418.10; -; 2.
DR InterPro; IPR001589; Actinin_actin-bd_CS.
DR InterPro; IPR001715; CH-domain.
DR InterPro; IPR011992; EF-hand-dom_pair.
DR InterPro; IPR014837; EF-hand_Ca_insen.
DR InterPro; IPR018247; EF_Hand_1_Ca_BS.
DR InterPro; IPR002048; EF_hand_dom.
DR InterPro; IPR018159; Spectrin/alpha-actinin.
DR InterPro; IPR002017; Spectrin_repeat.
DR Pfam; PF00307; CH; 2.
DR Pfam; PF13405; EF-hand_6; 1.
DR Pfam; PF08726; EFhand_Ca_insen; 1.
DR Pfam; PF00435; Spectrin; 4.
DR SMART; SM00033; CH; 2.
DR SMART; SM00054; EFh; 2.
DR SMART; SM00150; SPEC; 3.
DR SUPFAM; SSF47576; SSF47576; 1.
DR PROSITE; PS00019; ACTININ_1; 1.
DR PROSITE; PS00020; ACTININ_2; 1.
DR PROSITE; PS50021; CH; 2.
DR PROSITE; PS00018; EF_HAND_1; 1.
DR PROSITE; PS50222; EF_HAND_2; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Actin-binding; Alternative splicing;
KW Calcium; Cell junction; Cell membrane; Cell projection;
KW Complete proteome; Cytoplasm; Cytoskeleton; Direct protein sequencing;
KW Disease mutation; Membrane; Metal-binding; Phosphoprotein;
KW Polymorphism; Reference proteome; Repeat.
FT CHAIN 1 892 Alpha-actinin-1.
FT /FTId=PRO_0000073431.
FT DOMAIN 1 247 Actin-binding.
FT DOMAIN 31 135 CH 1.
FT DOMAIN 144 247 CH 2.
FT REPEAT 274 384 Spectrin 1.
FT REPEAT 394 499 Spectrin 2.
FT REPEAT 509 620 Spectrin 3.
FT REPEAT 630 733 Spectrin 4.
FT DOMAIN 746 781 EF-hand 1.
FT DOMAIN 787 822 EF-hand 2.
FT CA_BIND 759 770 Potential.
FT CA_BIND 800 811 Potential.
FT REGION 274 733 Interaction with DDN.
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 6 6 Phosphoserine.
FT MOD_RES 12 12 Phosphotyrosine; by FAK1.
FT MOD_RES 95 95 N6-acetyllysine.
FT MOD_RES 195 195 N6-acetyllysine.
FT MOD_RES 676 676 N6-acetyllysine.
FT VAR_SEQ 761 787 DHSGTLGPEEFKACLISLGYDIGNDPQ -> KKTGMMDTDD
FT FRACLISMGYNM (in isoform 2 and isoform
FT 4).
FT /FTId=VSP_041264.
FT VAR_SEQ 787 787 Q -> QKKTGMMDTDDFRACLISMGYNM (in isoform
FT 3).
FT /FTId=VSP_043525.
FT VAR_SEQ 840 840 K -> KLQEGGKMQTAHAAFTPPGFAAVSGRAALRLLDFAA
FT FLTTLSSQ (in isoform 4).
FT /FTId=VSP_047763.
FT VARIANT 32 32 Q -> K (in BDPLT15; the mutation
FT dominantly affects the actin filament
FT assembly likely resulting in abnormal
FT cytoskeletal organization).
FT /FTId=VAR_069910.
FT VARIANT 46 46 R -> Q (in BDPLT15).
FT /FTId=VAR_069911.
FT VARIANT 105 105 V -> I (in BDPLT15; the mutation
FT dominantly affects the actin filament
FT assembly likely resulting in abnormal
FT cytoskeletal organization).
FT /FTId=VAR_069912.
FT VARIANT 197 197 R -> W.
FT /FTId=VAR_069913.
FT VARIANT 225 225 E -> K (in BDPLT15).
FT /FTId=VAR_069914.
FT VARIANT 707 707 N -> T (in dbSNP:rs7157661).
FT /FTId=VAR_053883.
FT VARIANT 738 738 R -> W (in BDPLT15).
FT /FTId=VAR_069915.
FT VARIANT 752 752 R -> Q (in BDPLT15).
FT /FTId=VAR_069916.
FT VARIANT 868 868 T -> S (in dbSNP:rs11557769).
FT /FTId=VAR_053884.
FT CONFLICT 317 317 R -> L (in Ref. 11; CAA38970).
FT CONFLICT 321 321 R -> H (in Ref. 7; BAG58135).
FT CONFLICT 424 424 T -> A (in Ref. 7; BAG58135).
FT CONFLICT 477 477 Q -> L (in Ref. 11; CAA38970).
FT CONFLICT 630 631 RL -> SV (in Ref. 1; CAA33803).
FT CONFLICT 654 656 GRI -> ARF (in Ref. 11; CAA38970).
FT CONFLICT 674 674 Y -> D (in Ref. 11; CAA38970).
FT CONFLICT 778 778 L -> S (in Ref. 11; CAA38970).
FT HELIX 30 45
FT HELIX 46 48
FT TURN 55 61
FT HELIX 63 73
FT HELIX 86 102
FT HELIX 112 116
FT HELIX 120 135
FT TURN 136 138
FT HELIX 146 158
FT STRAND 168 170
FT HELIX 171 173
FT HELIX 177 186
FT HELIX 188 190
FT HELIX 193 195
FT HELIX 201 215
FT HELIX 224 229
FT STRAND 230 232
FT HELIX 235 249
SQ SEQUENCE 892 AA; 103058 MW; 6DA3E4D1A0289519 CRC64;
MDHYDSQQTN DYMQPEEDWD RDLLLDPAWE KQQRKTFTAW CNSHLRKAGT QIENIEEDFR
DGLKLMLLLE VISGERLAKP ERGKMRVHKI SNVNKALDFI ASKGVKLVSI GAEEIVDGNV
KMTLGMIWTI ILRFAIQDIS VEETSAKEGL LLWCQRKTAP YKNVNIQNFH ISWKDGLGFC
ALIHRHRPEL IDYGKLRKDD PLTNLNTAFD VAEKYLDIPK MLDAEDIVGT ARPDEKAIMT
YVSSFYHAFS GAQKAETAAN RICKVLAVNQ ENEQLMEDYE KLASDLLEWI RRTIPWLENR
VPENTMHAMQ QKLEDFRDYR RLHKPPKVQE KCQLEINFNT LQTKLRLSNR PAFMPSEGRM
VSDINNAWGC LEQVEKGYEE WLLNEIRRLE RLDHLAEKFR QKASIHEAWT DGKEAMLRQK
DYETATLSEI KALLKKHEAF ESDLAAHQDR VEQIAAIAQE LNELDYYDSP SVNARCQKIC
DQWDNLGALT QKRREALERT EKLLETIDQL YLEYAKRAAP FNNWMEGAME DLQDTFIVHT
IEEIQGLTTA HEQFKATLPD ADKERLAILG IHNEVSKIVQ TYHVNMAGTN PYTTITPQEI
NGKWDHVRQL VPRRDQALTE EHARQQHNER LRKQFGAQAN VIGPWIQTKM EEIGRISIEM
HGTLEDQLSH LRQYEKSIVN YKPKIDQLEG DHQLIQEALI FDNKHTNYTM EHIRVGWEQL
LTTIARTINE VENQILTRDA KGISQEQMNE FRASFNHFDR DHSGTLGPEE FKACLISLGY
DIGNDPQGEA EFARIMSIVD PNRLGVVTFQ AFIDFMSRET ADTDTADQVM ASFKILAGDK
NYITMDELRR ELPPDQAEYC IARMAPYTGP DSVPGALDYM SFSTALYGES DL
//
ID ACTN1_HUMAN Reviewed; 892 AA.
AC P12814; B3V8S3; B4DHH3; B7TY16; Q1HE25; Q9BTN1;
DT 01-OCT-1989, integrated into UniProtKB/Swiss-Prot.
read moreDT 13-APR-2004, sequence version 2.
DT 22-JAN-2014, entry version 172.
DE RecName: Full=Alpha-actinin-1;
DE AltName: Full=Alpha-actinin cytoskeletal isoform;
DE AltName: Full=F-actin cross-linking protein;
DE AltName: Full=Non-muscle alpha-actinin-1;
GN Name=ACTN1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Placenta;
RX PubMed=2780298; DOI=10.1093/nar/17.16.6725;
RA Millake D.B., Blanchard A.D., Patel B., Critchley D.R.;
RT "The cDNA sequence of a human placental alpha-actinin.";
RL Nucleic Acids Res. 17:6725-6725(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=2349951;
RA Youssoufian H., McAfee M., Kwiatkowski D.J.;
RT "Cloning and chromosomal localization of the human cytoskeletal alpha-
RT actinin gene reveals linkage to the beta-spectrin gene.";
RL Am. J. Hum. Genet. 47:62-71(1990).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RX PubMed=18353764; DOI=10.1074/mcp.M700590-MCP200;
RA Thorsen K., Sorensen K.D., Brems-Eskildsen A.S., Modin C.,
RA Gaustadnes M., Hein A.M., Kruhoffer M., Laurberg S., Borre M.,
RA Wang K., Brunak S., Krainer A.R., Torring N., Dyrskjot L.,
RA Andersen C.L., Orntoft T.F.;
RT "Alternative splicing in colon, bladder, and prostate cancer
RT identified by exon array analysis.";
RL Mol. Cell. Proteomics 7:1214-1224(2008).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
RC TISSUE=Tongue;
RA Mancini U.M., Tajara E.H.;
RT "A new mRNA isoform from ACTN1 gene.";
RL Submitted (APR-2006) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4).
RA Mansilla F., Orntoft T.F., Birkenkamp-Demtroeder K.;
RT "Actinin alpha 1 alternative splicing variant.";
RL Submitted (OCT-2008) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Brain;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12508121; DOI=10.1038/nature01348;
RA Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C.,
RA Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A.,
RA Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S.,
RA Sun H., Du H., Pepin K., Artiguenave F., Robert C., Cruaud C.,
RA Bruels T., Jaillon O., Friedlander L., Samson G., Brottier P.,
RA Cure S., Segurens B., Aniere F., Samain S., Crespeau H., Abbasi N.,
RA Aiach N., Boscus D., Dickhoff R., Dors M., Dubois I., Friedman C.,
RA Gouyvenoux M., James R., Madan A., Mairey-Estrada B., Mangenot S.,
RA Martins N., Menard M., Oztas S., Ratcliffe A., Shaffer T., Trask B.,
RA Vacherie B., Bellemere C., Belser C., Besnard-Gonnet M.,
RA Bartol-Mavel D., Boutard M., Briez-Silla S., Combette S.,
RA Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C., Muselet D.,
RA Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P., Trybou A.,
RA Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M.,
RA Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V.,
RA Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L.,
RA Verdier J., Verdier-Discala C., Hillier L.W., Fulton L., McPherson J.,
RA Matsuda F., Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W.,
RA Quetier F., Waterston R., Hood L., Weissenbach J.;
RT "The DNA sequence and analysis of human chromosome 14.";
RL Nature 421:601-607(2003).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Colon, and Skin;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [11]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 297-892 (ISOFORM 1).
RX PubMed=2169343;
RA Nishiyama M., Ozturk M., Frohlich M., Mafune K., Steele G. Jr.,
RA Wands J.R.;
RT "Expression of human alpha-actinin in human hepatocellular
RT carcinoma.";
RL Cancer Res. 50:6291-6294(1990).
RN [12]
RP PROTEIN SEQUENCE OF 1-21.
RC TISSUE=Platelet;
RX PubMed=12665801; DOI=10.1038/nbt810;
RA Gevaert K., Goethals M., Martens L., Van Damme J., Staes A.,
RA Thomas G.R., Vandekerckhove J.;
RT "Exploring proteomes and analyzing protein processing by mass
RT spectrometric identification of sorted N-terminal peptides.";
RL Nat. Biotechnol. 21:566-569(2003).
RN [13]
RP PROTEIN SEQUENCE OF 134-146.
RX PubMed=8713105; DOI=10.1006/bbrc.1996.1082;
RA Egerton M., Moritz R.L., Druker B., Kelso A., Simpson R.J.;
RT "Identification of the 70kD heat shock cognate protein (Hsc70) and
RT alpha-actinin-1 as novel phosphotyrosine-containing proteins in T
RT lymphocytes.";
RL Biochem. Biophys. Res. Commun. 224:666-674(1996).
RN [14]
RP PROTEIN SEQUENCE OF 566-577; 727-738 AND 835-863, AND SUBCELLULAR
RP LOCATION.
RX PubMed=7750553; DOI=10.1016/0014-5793(95)00362-D;
RA Dubernard V., Faucher D., Launay J.-M., Legrand C.;
RT "Identification of the cytoskeletal protein alpha-actinin as a
RT platelet thrombospondin-binding protein.";
RL FEBS Lett. 364:109-114(1995).
RN [15]
RP INTERACTION WITH TTID.
RX PubMed=10369880; DOI=10.1093/hmg/8.7.1329;
RA Salmikangas P., Mykkaenen O.M., Groenholm M., Heiska L., Kere J.,
RA Carpen O.;
RT "Myotilin, a novel sarcomeric protein with two Ig-like domains, is
RT encoded by a candidate gene for limb-girdle muscular dystrophy.";
RL Hum. Mol. Genet. 8:1329-1336(1999).
RN [16]
RP INTERACTION WITH MYOZ2.
RX PubMed=11114196; DOI=10.1073/pnas.260501097;
RA Frey N., Richardson J.A., Olson E.N.;
RT "Calsarcins, a novel family of sarcomeric calcineurin-binding
RT proteins.";
RL Proc. Natl. Acad. Sci. U.S.A. 97:14632-14637(2000).
RN [17]
RP PHOSPHORYLATION AT TYR-12.
RX PubMed=11369769; DOI=10.1074/jbc.M101678200;
RA Izaguirre G., Aguirre L., Hu Y.P., Lee H.Y., Schlaepfer D.D.,
RA Aneskievich B.J., Haimovich B.;
RT "The cytoskeletal/non-muscle isoform of alpha-actinin is
RT phosphorylated on its actin-binding domain by the focal adhesion
RT kinase.";
RL J. Biol. Chem. 276:28676-28685(2001).
RN [18]
RP INTERACTION WITH LPP.
RX PubMed=12615977; DOI=10.1242/jcs.00309;
RA Li B., Zhuang L., Reinhard M., Trueb B.;
RT "The lipoma preferred partner LPP interacts with alpha-actinin.";
RL J. Cell Sci. 116:1359-1366(2003).
RN [19]
RP INTERACTION WITH DDN.
RX PubMed=16464232; DOI=10.1111/j.1471-4159.2006.03679.x;
RA Kremerskothen J., Kindler S., Finger I., Veltel S., Barnekow A.;
RT "Postsynaptic recruitment of Dendrin depends on both dendritic mRNA
RT transport and synaptic anchoring.";
RL J. Neurochem. 96:1659-1666(2006).
RN [20]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-95; LYS-195 AND LYS-676, AND
RP MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [21]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [22]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, PHOSPHORYLATION [LARGE
RP SCALE ANALYSIS] AT SER-6, AND MASS SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [23]
RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 30-253.
RX PubMed=16698282; DOI=10.1016/j.jsb.2006.01.013;
RA Borrego-Diaz E., Kerff F., Lee S.H., Ferron F., Li Y., Dominguez R.;
RT "Crystal structure of the actin-binding domain of alpha-actinin 1:
RT evaluating two competing actin-binding models.";
RL J. Struct. Biol. 155:230-238(2006).
RN [24]
RP VARIANTS BDPLT15 LYS-32; GLN-46; ILE-105; LYS-225; TRP-738 AND
RP GLN-752, VARIANT TRP-197, AND CHARACTERIZATION OF VARIANTS BDPLT15
RP LYS-32 AND ILE-105.
RX PubMed=23434115; DOI=10.1016/j.ajhg.2013.01.015;
RA Kunishima S., Okuno Y., Yoshida K., Shiraishi Y., Sanada M.,
RA Muramatsu H., Chiba K., Tanaka H., Miyazaki K., Sakai M., Ohtake M.,
RA Kobayashi R., Iguchi A., Niimi G., Otsu M., Takahashi Y., Miyano S.,
RA Saito H., Kojima S., Ogawa S.;
RT "ACTN1 mutations cause congenital macrothrombocytopenia.";
RL Am. J. Hum. Genet. 92:431-438(2013).
CC -!- FUNCTION: F-actin cross-linking protein which is thought to anchor
CC actin to a variety of intracellular structures. This is a bundling
CC protein.
CC -!- SUBUNIT: Homodimer; antiparallel. Interacts with DDN, MYOZ2,
CC PDLIM2, TTID and LPP. Interacts with PSD. Interacts with MICALL2
CC (By similarity).
CC -!- INTERACTION:
CC P12931:SRC; NbExp=2; IntAct=EBI-351710, EBI-621482;
CC Q8VC66:Ssx2ip (xeno); NbExp=3; IntAct=EBI-351710, EBI-6654049;
CC Q8WZ42:TTN; NbExp=2; IntAct=EBI-351710, EBI-681210;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton. Cytoplasm,
CC myofibril, sarcomere, Z line. Cell membrane (By similarity). Cell
CC junction (By similarity). Cell projection, ruffle (By similarity).
CC Note=Colocalizes with MYOZ2 and PPP3CA at the Z-line of heart and
CC skeletal muscle. Colocalizes with PSD in membrane ruffles and
CC central reticular structures (By similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1;
CC IsoId=P12814-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P12814-2; Sequence=VSP_041264;
CC Name=3;
CC IsoId=P12814-3; Sequence=VSP_043525;
CC Name=4;
CC IsoId=P12814-4; Sequence=VSP_041264, VSP_047763;
CC -!- DISEASE: Bleeding disorder, platelet-type 15 (BDPLT15)
CC [MIM:615193]: An autosomal dominant form of macrothrombocytopenia.
CC Affected individuals usually have no or only mild bleeding
CC tendency, such as epistaxis. Laboratory studies show decreased
CC numbers of large platelets and anisocytosis, but the platelets
CC show no in vitro functional abnormalities. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the alpha-actinin family.
CC -!- SIMILARITY: Contains 1 actin-binding domain.
CC -!- SIMILARITY: Contains 2 CH (calponin-homology) domains.
CC -!- SIMILARITY: Contains 2 EF-hand domains.
CC -!- SIMILARITY: Contains 4 spectrin repeats.
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DR EMBL; X15804; CAA33803.1; -; mRNA.
DR EMBL; M95178; AAA51582.1; -; mRNA.
DR EMBL; EU716325; ACE62922.1; -; mRNA.
DR EMBL; DQ496098; ABF50047.1; -; mRNA.
DR EMBL; FJ410030; ACJ24535.1; -; mRNA.
DR EMBL; BT007207; AAP35871.1; -; mRNA.
DR EMBL; AK295099; BAG58135.1; -; mRNA.
DR EMBL; AL117694; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471061; EAW80975.1; -; Genomic_DNA.
DR EMBL; BC003576; AAH03576.1; -; mRNA.
DR EMBL; BC015766; AAH15766.1; -; mRNA.
DR EMBL; X55187; CAA38970.1; -; mRNA.
DR PIR; S05503; FAHUAA.
DR RefSeq; NP_001093.1; NM_001102.3.
DR RefSeq; NP_001123476.1; NM_001130004.1.
DR RefSeq; NP_001123477.1; NM_001130005.1.
DR RefSeq; XP_005268207.1; XM_005268150.1.
DR UniGene; Hs.509765; -.
DR PDB; 2EYI; X-ray; 1.70 A; A=30-253.
DR PDB; 2EYN; X-ray; 1.80 A; A=30-253.
DR PDBsum; 2EYI; -.
DR PDBsum; 2EYN; -.
DR ProteinModelPortal; P12814; -.
DR SMR; P12814; 30-254, 267-892.
DR DIP; DIP-33184N; -.
DR IntAct; P12814; 36.
DR MINT; MINT-215335; -.
DR STRING; 9606.ENSP00000377941; -.
DR PhosphoSite; P12814; -.
DR DMDM; 46397817; -.
DR OGP; P12814; -.
DR PaxDb; P12814; -.
DR PeptideAtlas; P12814; -.
DR PRIDE; P12814; -.
DR DNASU; 87; -.
DR Ensembl; ENST00000193403; ENSP00000193403; ENSG00000072110.
DR Ensembl; ENST00000394419; ENSP00000377941; ENSG00000072110.
DR Ensembl; ENST00000438964; ENSP00000414272; ENSG00000072110.
DR Ensembl; ENST00000538545; ENSP00000439828; ENSG00000072110.
DR GeneID; 87; -.
DR KEGG; hsa:87; -.
DR UCSC; uc001xkk.3; human.
DR CTD; 87; -.
DR GeneCards; GC14M069341; -.
DR HGNC; HGNC:163; ACTN1.
DR HPA; CAB004303; -.
DR HPA; HPA006035; -.
DR MIM; 102575; gene.
DR MIM; 615193; phenotype.
DR neXtProt; NX_P12814; -.
DR Orphanet; 140957; Autosomal dominant macrothrombocytopenia.
DR PharmGKB; PA24; -.
DR eggNOG; COG5069; -.
DR HOGENOM; HOG000263418; -.
DR HOVERGEN; HBG050453; -.
DR KO; K05699; -.
DR OMA; WIRRTMP; -.
DR OrthoDB; EOG72C4ZJ; -.
DR Reactome; REACT_111155; Cell-Cell communication.
DR Reactome; REACT_118779; Extracellular matrix organization.
DR Reactome; REACT_604; Hemostasis.
DR ChiTaRS; ACTN1; human.
DR EvolutionaryTrace; P12814; -.
DR GeneWiki; Actinin,_alpha_1; -.
DR GenomeRNAi; 87; -.
DR NextBio; 323; -.
DR PRO; PR:P12814; -.
DR ArrayExpress; P12814; -.
DR Bgee; P12814; -.
DR CleanEx; HS_ACTN1; -.
DR Genevestigator; P12814; -.
DR GO; GO:0005856; C:cytoskeleton; IEA:UniProtKB-SubCell.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0043197; C:dendritic spine; IEA:Ensembl.
DR GO; GO:0070062; C:extracellular vesicular exosome; IDA:UniProtKB.
DR GO; GO:0005916; C:fascia adherens; IEA:Ensembl.
DR GO; GO:0005925; C:focal adhesion; IMP:UniProtKB.
DR GO; GO:0005634; C:nucleus; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0031093; C:platelet alpha granule lumen; TAS:Reactome.
DR GO; GO:0031143; C:pseudopodium; TAS:UniProtKB.
DR GO; GO:0001726; C:ruffle; IEA:UniProtKB-SubCell.
DR GO; GO:0030018; C:Z disc; IEA:UniProtKB-SubCell.
DR GO; GO:0005509; F:calcium ion binding; IEA:InterPro.
DR GO; GO:0003725; F:double-stranded RNA binding; IDA:MGI.
DR GO; GO:0005178; F:integrin binding; IDA:UniProtKB.
DR GO; GO:0051017; P:actin filament bundle assembly; IEA:Ensembl.
DR GO; GO:0030198; P:extracellular matrix organization; TAS:Reactome.
DR GO; GO:0048041; P:focal adhesion assembly; IMP:UniProtKB.
DR GO; GO:0051271; P:negative regulation of cellular component movement; IMP:UniProtKB.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0002576; P:platelet degranulation; TAS:Reactome.
DR GO; GO:0042981; P:regulation of apoptotic process; NAS:UniProtKB.
DR Gene3D; 1.10.238.10; -; 2.
DR Gene3D; 1.10.418.10; -; 2.
DR InterPro; IPR001589; Actinin_actin-bd_CS.
DR InterPro; IPR001715; CH-domain.
DR InterPro; IPR011992; EF-hand-dom_pair.
DR InterPro; IPR014837; EF-hand_Ca_insen.
DR InterPro; IPR018247; EF_Hand_1_Ca_BS.
DR InterPro; IPR002048; EF_hand_dom.
DR InterPro; IPR018159; Spectrin/alpha-actinin.
DR InterPro; IPR002017; Spectrin_repeat.
DR Pfam; PF00307; CH; 2.
DR Pfam; PF13405; EF-hand_6; 1.
DR Pfam; PF08726; EFhand_Ca_insen; 1.
DR Pfam; PF00435; Spectrin; 4.
DR SMART; SM00033; CH; 2.
DR SMART; SM00054; EFh; 2.
DR SMART; SM00150; SPEC; 3.
DR SUPFAM; SSF47576; SSF47576; 1.
DR PROSITE; PS00019; ACTININ_1; 1.
DR PROSITE; PS00020; ACTININ_2; 1.
DR PROSITE; PS50021; CH; 2.
DR PROSITE; PS00018; EF_HAND_1; 1.
DR PROSITE; PS50222; EF_HAND_2; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Actin-binding; Alternative splicing;
KW Calcium; Cell junction; Cell membrane; Cell projection;
KW Complete proteome; Cytoplasm; Cytoskeleton; Direct protein sequencing;
KW Disease mutation; Membrane; Metal-binding; Phosphoprotein;
KW Polymorphism; Reference proteome; Repeat.
FT CHAIN 1 892 Alpha-actinin-1.
FT /FTId=PRO_0000073431.
FT DOMAIN 1 247 Actin-binding.
FT DOMAIN 31 135 CH 1.
FT DOMAIN 144 247 CH 2.
FT REPEAT 274 384 Spectrin 1.
FT REPEAT 394 499 Spectrin 2.
FT REPEAT 509 620 Spectrin 3.
FT REPEAT 630 733 Spectrin 4.
FT DOMAIN 746 781 EF-hand 1.
FT DOMAIN 787 822 EF-hand 2.
FT CA_BIND 759 770 Potential.
FT CA_BIND 800 811 Potential.
FT REGION 274 733 Interaction with DDN.
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 6 6 Phosphoserine.
FT MOD_RES 12 12 Phosphotyrosine; by FAK1.
FT MOD_RES 95 95 N6-acetyllysine.
FT MOD_RES 195 195 N6-acetyllysine.
FT MOD_RES 676 676 N6-acetyllysine.
FT VAR_SEQ 761 787 DHSGTLGPEEFKACLISLGYDIGNDPQ -> KKTGMMDTDD
FT FRACLISMGYNM (in isoform 2 and isoform
FT 4).
FT /FTId=VSP_041264.
FT VAR_SEQ 787 787 Q -> QKKTGMMDTDDFRACLISMGYNM (in isoform
FT 3).
FT /FTId=VSP_043525.
FT VAR_SEQ 840 840 K -> KLQEGGKMQTAHAAFTPPGFAAVSGRAALRLLDFAA
FT FLTTLSSQ (in isoform 4).
FT /FTId=VSP_047763.
FT VARIANT 32 32 Q -> K (in BDPLT15; the mutation
FT dominantly affects the actin filament
FT assembly likely resulting in abnormal
FT cytoskeletal organization).
FT /FTId=VAR_069910.
FT VARIANT 46 46 R -> Q (in BDPLT15).
FT /FTId=VAR_069911.
FT VARIANT 105 105 V -> I (in BDPLT15; the mutation
FT dominantly affects the actin filament
FT assembly likely resulting in abnormal
FT cytoskeletal organization).
FT /FTId=VAR_069912.
FT VARIANT 197 197 R -> W.
FT /FTId=VAR_069913.
FT VARIANT 225 225 E -> K (in BDPLT15).
FT /FTId=VAR_069914.
FT VARIANT 707 707 N -> T (in dbSNP:rs7157661).
FT /FTId=VAR_053883.
FT VARIANT 738 738 R -> W (in BDPLT15).
FT /FTId=VAR_069915.
FT VARIANT 752 752 R -> Q (in BDPLT15).
FT /FTId=VAR_069916.
FT VARIANT 868 868 T -> S (in dbSNP:rs11557769).
FT /FTId=VAR_053884.
FT CONFLICT 317 317 R -> L (in Ref. 11; CAA38970).
FT CONFLICT 321 321 R -> H (in Ref. 7; BAG58135).
FT CONFLICT 424 424 T -> A (in Ref. 7; BAG58135).
FT CONFLICT 477 477 Q -> L (in Ref. 11; CAA38970).
FT CONFLICT 630 631 RL -> SV (in Ref. 1; CAA33803).
FT CONFLICT 654 656 GRI -> ARF (in Ref. 11; CAA38970).
FT CONFLICT 674 674 Y -> D (in Ref. 11; CAA38970).
FT CONFLICT 778 778 L -> S (in Ref. 11; CAA38970).
FT HELIX 30 45
FT HELIX 46 48
FT TURN 55 61
FT HELIX 63 73
FT HELIX 86 102
FT HELIX 112 116
FT HELIX 120 135
FT TURN 136 138
FT HELIX 146 158
FT STRAND 168 170
FT HELIX 171 173
FT HELIX 177 186
FT HELIX 188 190
FT HELIX 193 195
FT HELIX 201 215
FT HELIX 224 229
FT STRAND 230 232
FT HELIX 235 249
SQ SEQUENCE 892 AA; 103058 MW; 6DA3E4D1A0289519 CRC64;
MDHYDSQQTN DYMQPEEDWD RDLLLDPAWE KQQRKTFTAW CNSHLRKAGT QIENIEEDFR
DGLKLMLLLE VISGERLAKP ERGKMRVHKI SNVNKALDFI ASKGVKLVSI GAEEIVDGNV
KMTLGMIWTI ILRFAIQDIS VEETSAKEGL LLWCQRKTAP YKNVNIQNFH ISWKDGLGFC
ALIHRHRPEL IDYGKLRKDD PLTNLNTAFD VAEKYLDIPK MLDAEDIVGT ARPDEKAIMT
YVSSFYHAFS GAQKAETAAN RICKVLAVNQ ENEQLMEDYE KLASDLLEWI RRTIPWLENR
VPENTMHAMQ QKLEDFRDYR RLHKPPKVQE KCQLEINFNT LQTKLRLSNR PAFMPSEGRM
VSDINNAWGC LEQVEKGYEE WLLNEIRRLE RLDHLAEKFR QKASIHEAWT DGKEAMLRQK
DYETATLSEI KALLKKHEAF ESDLAAHQDR VEQIAAIAQE LNELDYYDSP SVNARCQKIC
DQWDNLGALT QKRREALERT EKLLETIDQL YLEYAKRAAP FNNWMEGAME DLQDTFIVHT
IEEIQGLTTA HEQFKATLPD ADKERLAILG IHNEVSKIVQ TYHVNMAGTN PYTTITPQEI
NGKWDHVRQL VPRRDQALTE EHARQQHNER LRKQFGAQAN VIGPWIQTKM EEIGRISIEM
HGTLEDQLSH LRQYEKSIVN YKPKIDQLEG DHQLIQEALI FDNKHTNYTM EHIRVGWEQL
LTTIARTINE VENQILTRDA KGISQEQMNE FRASFNHFDR DHSGTLGPEE FKACLISLGY
DIGNDPQGEA EFARIMSIVD PNRLGVVTFQ AFIDFMSRET ADTDTADQVM ASFKILAGDK
NYITMDELRR ELPPDQAEYC IARMAPYTGP DSVPGALDYM SFSTALYGES DL
//
MIM
102575
*RECORD*
*FIELD* NO
102575
*FIELD* TI
*102575 ACTININ, ALPHA-1; ACTN1
*FIELD* TX
DESCRIPTION
Alpha-actinin was initially isolated from rabbit skeletal muscle as a
read morefactor that induces the gelation of F-actin and promotes the
superprecipitation of actomyosin. Subsequently, a number of different
isoforms were isolated from both muscle and nonmuscle cells and from a
wide variety of organisms. The native molecule is thought to be a
homodimer of 97-kD subunits arranged in antiparallel fashion. In
myofibrillar cells, alpha-actinin constitutes a major component of Z
discs in striated muscle and of the functionally analogous dense bodies
and dense plaques in smooth muscle. In nonmuscle cells, it is
distributed along microfilament bundles and is thought to mediate their
attachment to the membrane at adherens-type junctions (Youssoufian et
al., 1990).
CLONING
Youssoufian et al. (1990) cloned and characterized a full-length cDNA
encoding the human cytoskeletal isoform. The gene encodes 891 amino
acids with 96 to 98% sequence identity at the amino acid level to
chicken nonskeletal muscle alpha-actinin. Transient expression in COS
cells produced a protein of about 104 kD.
GENE FUNCTION
Kanchanawong et al. (2010) used 3-dimensional super-resolution
fluorescence microscopy to map nanoscale protein organization in focal
adhesions. Their results revealed that integrins and actin are
vertically separated by an approximately 40-nm focal adhesion core
region consisting of multiple protein-specific strata: a
membrane-apposed integrin signaling layer containing integrin
cytoplasmic tails (see 193210), focal adhesion kinase (600758), and
paxillin (602505); an intermediate force-transduction layer containing
talin (186745) and vinculin (193065); and an uppermost actin-regulatory
layer containing zyxin (602002), vasodilator-stimulated phosphoprotein
(601703), and alpha-actinin. By localizing amino- and carboxy-terminally
tagged talins, Kanchanawong et al. (2010) revealed talin's polarized
orientation, indicative of a role in organizing the focal adhesion
strata. Kanchanawong et al. (2010) concluded that their composite
multilaminar protein architecture provided a molecular blueprint for
understanding focal adhesion functions.
MAPPING
By analysis of somatic cell hybrids and by in situ hybridization,
Youssoufian et al. (1990) mapped the gene to 14q22-q24. Pulsed-field gel
analysis of genomic DNA showed that the ACTN1 gene and that for
erythroid beta-spectrin (SPTB; 182870) are located in the same
restriction fragment. This finding is of great interest because of the
structural homology between spectrin and actinin.
MOLECULAR GENETICS
In affected members from 6 unrelated Japanese families with autosomal
dominant platelet-type bleeding disorder-15 (BDPLT15; 615193), manifest
mainly as macrothrombocytopenia with little bleeding, Kunishima et al.
(2013) identified 6 different heterozygous missense mutations in the
ACTN1 gene (102575.0001-102575.0006). Three of the mutations were
identified by exome sequencing. ACTN1 mutations were found in 5.5% of
the dominant forms of congenital macrothrombocytopenia in their cohort,
and represented the fourth most common cause of the disorder in Japanese
individuals. Expression of the mutations in Chinese hamster ovary (CHO)
cells showed that the mutant proteins caused varying degrees of
disorganization of the actin filaments, with mutant ACTN1 colocalized
with less fine, shortened actin filaments, and unbound ACTN1 coarsely
distributed within the cytoplasm. Expression of 2 of the mutations
(V105I, 102575.0001 and G32K, 102575.0002) in mouse fetal liver-derived
megakaryocytes resulted in less organization of the circumferential
actin-filament network compared to controls. The findings suggested that
ACTN1 mutations dominantly affected the actin filament assembly, likely
resulting in abnormal cytoskeletal organization. Examination of
proplatelet formation from megakaryocytes showed that the G32K and V105I
mutations did not change the rate of proplatelet formation or platelet
production, but did reduce the number of proplatelet tips and increase
the size of proplatelet tips from megakaryocytes.
*FIELD* AV
.0001
BLEEDING DISORDER, PLATELET-TYPE, 15
ACTN1, VAL105ILE
In a Japanese mother and daughter with platelet-type bleeding
disorder-15 (BDPLT15; 615193) manifest as macrothrombocytopenia,
Kunishima et al. (2013) identified a heterozygous 313G-A transition in
exon 3 of the ACTN1 gene, resulting in a val105-to-ile (V105I)
substitution at a highly conserved residue in the functional N-terminal
actin-binding domain. The mutation, which was found by exome sequencing,
was not found in several large control databases or in 120 control
individuals. Expression of the mutation in CHO cells showed that the
mutant protein caused varying degrees of disorganization of the actin
filaments, with mutant ACTN1 colocalized with less fine, shortened actin
filaments and unbound ACTN1 coarsely distributed within the cytoplasm.
Expression of the mutation in mouse fetal liver-derived megakaryocytes
showed less organization of the circumferential actin-filament network
compared to controls. The findings suggested that the mutation
dominantly affected the actin filament assembly, likely resulting in
abnormal cytoskeletal organization. Examination of proplatelet formation
from megakaryocytes showed that the mutation did not change the rate of
proplatelet formation or platelet production, but did reduce the number
of proplatelet tips and increase the size of proplatelet tips from
megakaryocytes.
.0002
BLEEDING DISORDER, PLATELET-TYPE, 15
ACTN1, GLN32LYS
In a Japanese father and his 2 sons with BDPLT15 (615193) manifest as
macrothrombocytopenia, Kunishima et al. (2013) identified a heterozygous
94C-A transversion in exon 1 of the ACTN1 gene, resulting in a
gln32-to-lys (Q32K) substitution at a highly conserved residue in the
functional N-terminal actin-binding domain. The mutation, which was
found by exome sequencing, was not found in several large control
databases or in 120 control individuals. Expression of the mutation in
CHO cells showed that the mutant protein caused varying degrees of
disorganization of the actin filaments, with mutant ACTN1 colocalized
with less fine, shortened actin filaments and unbound ACTN1 coarsely
distributed within the cytoplasm. Expression of the mutation in mouse
fetal liver-derived megakaryocytes showed less organization of the
circumferential actin-filament network compared to controls. The
findings suggested that the mutation dominantly affected the actin
filament assembly, likely resulting in abnormal cytoskeletal
organization. Examination of proplatelet formation from megakaryocytes
showed that the mutation did not change the rate of proplatelet
formation or platelet production, but did reduce the number of
proplatelet tips and increase the size of proplatelet tips from
megakaryocytes.
.0003
BLEEDING DISORDER, PLATELET-TYPE, 15
ACTN1, ARG752GLN
In a Japanese mother and son with BDPLT15 (615193) manifest as
macrothrombocytopenia, Kunishima et al. (2013) identified a heterozygous
2255G-A transition in exon 18 of the ACTN1 gene, resulting in an
arg752-to-gln (R752Q) substitution at a highly conserved residue in the
functional C-terminal calmodulin-like domain. The mutation, which was
identified by sequencing, was not found in several large control
databases or in 120 control individuals.
.0004
BLEEDING DISORDER, PLATELET-TYPE, 15
ACTN1, ARG46GLN
In a Japanese father and his 2 daughters with BDPLT15 (615193) manifest
as macrothrombocytopenia, Kunishima et al. (2013) identified a
heterozygous 137G-A transition in exon 2 of the ACTN1 gene, resulting in
an arg46-to-gln (R46Q) substitution at a highly conserved residue in the
functional N-terminal actin-binding domain. The mutation was not found
in 120 control individuals.
.0005
BLEEDING DISORDER, PLATELET-TYPE, 15
ACTN1, ARG738TRP
In a Japanese patient with BDPLT15 (615193) manifest as
macrothrombocytopenia, Kunishima et al. (2013) identified a heterozygous
2212C-T transition in exon 18 of the ACTN1 gene, resulting in an
arg738-to-trp (R738W) substitution at a highly conserved residue in the
functional C-terminal calmodulin-binding domain. There was a family
history of the disorder, but DNA from other family members was not
available. The mutation was not found in 120 control individuals.
.0006
BLEEDING DISORDER, PLATELET-TYPE, 15
ACTN1, GLU225LYS
In a Japanese mother and daughter with BDPLT15 (615193) manifest as
macrothrombocytopenia, Kunishima et al. (2013) identified a heterozygous
673G-A transition in exon 7 of the ACTN1 gene, resulting in a
glu225-to-lys (E225K) substitution at a highly conserved residue in the
functional N-terminal actin-binding domain. The mutation was not found
in 120 control individuals.
*FIELD* RF
1. Kanchanawong, P.; Shtengel, G.; Pasapera, A. M.; Ramko, E. B.;
Davidson, M. W.; Hess, H. F.; Waterman, C. M.: Nanoscale architecture
of integrin-based cell adhesions. Nature 468: 580-584, 2010.
2. Kunishima, S.; Okuno, Y.; Yoshida, K.; Shiraishi, Y.; Sanada, M.;
Muramatsu, H.; Chiba, K.; Tanaka, H.; Miyazaki, K.; Sakai, M.; Ohtake,
M.; Kobayashi, R.; Iguchi, A.; Niimi, G.; Otsu, M.; Takahashi, Y.;
Miyano, S.; Saito, H.; Kojima, S.; Ogawa, S.: ACTN1 mutations cause
congenital macrothrombocytopenia. Am. J. Hum. Genet. 92: 431-438,
2013.
3. Youssoufian, H.; McAfee, M.; Kwiatkowski, D. J.: Cloning and chromosomal
localization of the human cytoskeletal alpha-actinin gene reveals
linkage to the beta-spectrin gene. Am. J. Hum. Genet. 47: 62-72,
1990.
*FIELD* CN
Cassandra L. Kniffin - updated: 4/23/2013
Ada Hamosh - updated: 2/2/2011
*FIELD* CD
Victor A. McKusick: 7/12/1990
*FIELD* ED
carol: 04/24/2013
ckniffin: 4/23/2013
alopez: 2/7/2011
terry: 2/2/2011
terry: 7/7/2008
wwang: 6/19/2008
terry: 6/16/2008
terry: 3/11/2005
mark: 4/10/1997
carol: 8/14/1992
supermim: 3/16/1992
carol: 8/20/1990
carol: 7/12/1990
*RECORD*
*FIELD* NO
102575
*FIELD* TI
*102575 ACTININ, ALPHA-1; ACTN1
*FIELD* TX
DESCRIPTION
Alpha-actinin was initially isolated from rabbit skeletal muscle as a
read morefactor that induces the gelation of F-actin and promotes the
superprecipitation of actomyosin. Subsequently, a number of different
isoforms were isolated from both muscle and nonmuscle cells and from a
wide variety of organisms. The native molecule is thought to be a
homodimer of 97-kD subunits arranged in antiparallel fashion. In
myofibrillar cells, alpha-actinin constitutes a major component of Z
discs in striated muscle and of the functionally analogous dense bodies
and dense plaques in smooth muscle. In nonmuscle cells, it is
distributed along microfilament bundles and is thought to mediate their
attachment to the membrane at adherens-type junctions (Youssoufian et
al., 1990).
CLONING
Youssoufian et al. (1990) cloned and characterized a full-length cDNA
encoding the human cytoskeletal isoform. The gene encodes 891 amino
acids with 96 to 98% sequence identity at the amino acid level to
chicken nonskeletal muscle alpha-actinin. Transient expression in COS
cells produced a protein of about 104 kD.
GENE FUNCTION
Kanchanawong et al. (2010) used 3-dimensional super-resolution
fluorescence microscopy to map nanoscale protein organization in focal
adhesions. Their results revealed that integrins and actin are
vertically separated by an approximately 40-nm focal adhesion core
region consisting of multiple protein-specific strata: a
membrane-apposed integrin signaling layer containing integrin
cytoplasmic tails (see 193210), focal adhesion kinase (600758), and
paxillin (602505); an intermediate force-transduction layer containing
talin (186745) and vinculin (193065); and an uppermost actin-regulatory
layer containing zyxin (602002), vasodilator-stimulated phosphoprotein
(601703), and alpha-actinin. By localizing amino- and carboxy-terminally
tagged talins, Kanchanawong et al. (2010) revealed talin's polarized
orientation, indicative of a role in organizing the focal adhesion
strata. Kanchanawong et al. (2010) concluded that their composite
multilaminar protein architecture provided a molecular blueprint for
understanding focal adhesion functions.
MAPPING
By analysis of somatic cell hybrids and by in situ hybridization,
Youssoufian et al. (1990) mapped the gene to 14q22-q24. Pulsed-field gel
analysis of genomic DNA showed that the ACTN1 gene and that for
erythroid beta-spectrin (SPTB; 182870) are located in the same
restriction fragment. This finding is of great interest because of the
structural homology between spectrin and actinin.
MOLECULAR GENETICS
In affected members from 6 unrelated Japanese families with autosomal
dominant platelet-type bleeding disorder-15 (BDPLT15; 615193), manifest
mainly as macrothrombocytopenia with little bleeding, Kunishima et al.
(2013) identified 6 different heterozygous missense mutations in the
ACTN1 gene (102575.0001-102575.0006). Three of the mutations were
identified by exome sequencing. ACTN1 mutations were found in 5.5% of
the dominant forms of congenital macrothrombocytopenia in their cohort,
and represented the fourth most common cause of the disorder in Japanese
individuals. Expression of the mutations in Chinese hamster ovary (CHO)
cells showed that the mutant proteins caused varying degrees of
disorganization of the actin filaments, with mutant ACTN1 colocalized
with less fine, shortened actin filaments, and unbound ACTN1 coarsely
distributed within the cytoplasm. Expression of 2 of the mutations
(V105I, 102575.0001 and G32K, 102575.0002) in mouse fetal liver-derived
megakaryocytes resulted in less organization of the circumferential
actin-filament network compared to controls. The findings suggested that
ACTN1 mutations dominantly affected the actin filament assembly, likely
resulting in abnormal cytoskeletal organization. Examination of
proplatelet formation from megakaryocytes showed that the G32K and V105I
mutations did not change the rate of proplatelet formation or platelet
production, but did reduce the number of proplatelet tips and increase
the size of proplatelet tips from megakaryocytes.
*FIELD* AV
.0001
BLEEDING DISORDER, PLATELET-TYPE, 15
ACTN1, VAL105ILE
In a Japanese mother and daughter with platelet-type bleeding
disorder-15 (BDPLT15; 615193) manifest as macrothrombocytopenia,
Kunishima et al. (2013) identified a heterozygous 313G-A transition in
exon 3 of the ACTN1 gene, resulting in a val105-to-ile (V105I)
substitution at a highly conserved residue in the functional N-terminal
actin-binding domain. The mutation, which was found by exome sequencing,
was not found in several large control databases or in 120 control
individuals. Expression of the mutation in CHO cells showed that the
mutant protein caused varying degrees of disorganization of the actin
filaments, with mutant ACTN1 colocalized with less fine, shortened actin
filaments and unbound ACTN1 coarsely distributed within the cytoplasm.
Expression of the mutation in mouse fetal liver-derived megakaryocytes
showed less organization of the circumferential actin-filament network
compared to controls. The findings suggested that the mutation
dominantly affected the actin filament assembly, likely resulting in
abnormal cytoskeletal organization. Examination of proplatelet formation
from megakaryocytes showed that the mutation did not change the rate of
proplatelet formation or platelet production, but did reduce the number
of proplatelet tips and increase the size of proplatelet tips from
megakaryocytes.
.0002
BLEEDING DISORDER, PLATELET-TYPE, 15
ACTN1, GLN32LYS
In a Japanese father and his 2 sons with BDPLT15 (615193) manifest as
macrothrombocytopenia, Kunishima et al. (2013) identified a heterozygous
94C-A transversion in exon 1 of the ACTN1 gene, resulting in a
gln32-to-lys (Q32K) substitution at a highly conserved residue in the
functional N-terminal actin-binding domain. The mutation, which was
found by exome sequencing, was not found in several large control
databases or in 120 control individuals. Expression of the mutation in
CHO cells showed that the mutant protein caused varying degrees of
disorganization of the actin filaments, with mutant ACTN1 colocalized
with less fine, shortened actin filaments and unbound ACTN1 coarsely
distributed within the cytoplasm. Expression of the mutation in mouse
fetal liver-derived megakaryocytes showed less organization of the
circumferential actin-filament network compared to controls. The
findings suggested that the mutation dominantly affected the actin
filament assembly, likely resulting in abnormal cytoskeletal
organization. Examination of proplatelet formation from megakaryocytes
showed that the mutation did not change the rate of proplatelet
formation or platelet production, but did reduce the number of
proplatelet tips and increase the size of proplatelet tips from
megakaryocytes.
.0003
BLEEDING DISORDER, PLATELET-TYPE, 15
ACTN1, ARG752GLN
In a Japanese mother and son with BDPLT15 (615193) manifest as
macrothrombocytopenia, Kunishima et al. (2013) identified a heterozygous
2255G-A transition in exon 18 of the ACTN1 gene, resulting in an
arg752-to-gln (R752Q) substitution at a highly conserved residue in the
functional C-terminal calmodulin-like domain. The mutation, which was
identified by sequencing, was not found in several large control
databases or in 120 control individuals.
.0004
BLEEDING DISORDER, PLATELET-TYPE, 15
ACTN1, ARG46GLN
In a Japanese father and his 2 daughters with BDPLT15 (615193) manifest
as macrothrombocytopenia, Kunishima et al. (2013) identified a
heterozygous 137G-A transition in exon 2 of the ACTN1 gene, resulting in
an arg46-to-gln (R46Q) substitution at a highly conserved residue in the
functional N-terminal actin-binding domain. The mutation was not found
in 120 control individuals.
.0005
BLEEDING DISORDER, PLATELET-TYPE, 15
ACTN1, ARG738TRP
In a Japanese patient with BDPLT15 (615193) manifest as
macrothrombocytopenia, Kunishima et al. (2013) identified a heterozygous
2212C-T transition in exon 18 of the ACTN1 gene, resulting in an
arg738-to-trp (R738W) substitution at a highly conserved residue in the
functional C-terminal calmodulin-binding domain. There was a family
history of the disorder, but DNA from other family members was not
available. The mutation was not found in 120 control individuals.
.0006
BLEEDING DISORDER, PLATELET-TYPE, 15
ACTN1, GLU225LYS
In a Japanese mother and daughter with BDPLT15 (615193) manifest as
macrothrombocytopenia, Kunishima et al. (2013) identified a heterozygous
673G-A transition in exon 7 of the ACTN1 gene, resulting in a
glu225-to-lys (E225K) substitution at a highly conserved residue in the
functional N-terminal actin-binding domain. The mutation was not found
in 120 control individuals.
*FIELD* RF
1. Kanchanawong, P.; Shtengel, G.; Pasapera, A. M.; Ramko, E. B.;
Davidson, M. W.; Hess, H. F.; Waterman, C. M.: Nanoscale architecture
of integrin-based cell adhesions. Nature 468: 580-584, 2010.
2. Kunishima, S.; Okuno, Y.; Yoshida, K.; Shiraishi, Y.; Sanada, M.;
Muramatsu, H.; Chiba, K.; Tanaka, H.; Miyazaki, K.; Sakai, M.; Ohtake,
M.; Kobayashi, R.; Iguchi, A.; Niimi, G.; Otsu, M.; Takahashi, Y.;
Miyano, S.; Saito, H.; Kojima, S.; Ogawa, S.: ACTN1 mutations cause
congenital macrothrombocytopenia. Am. J. Hum. Genet. 92: 431-438,
2013.
3. Youssoufian, H.; McAfee, M.; Kwiatkowski, D. J.: Cloning and chromosomal
localization of the human cytoskeletal alpha-actinin gene reveals
linkage to the beta-spectrin gene. Am. J. Hum. Genet. 47: 62-72,
1990.
*FIELD* CN
Cassandra L. Kniffin - updated: 4/23/2013
Ada Hamosh - updated: 2/2/2011
*FIELD* CD
Victor A. McKusick: 7/12/1990
*FIELD* ED
carol: 04/24/2013
ckniffin: 4/23/2013
alopez: 2/7/2011
terry: 2/2/2011
terry: 7/7/2008
wwang: 6/19/2008
terry: 6/16/2008
terry: 3/11/2005
mark: 4/10/1997
carol: 8/14/1992
supermim: 3/16/1992
carol: 8/20/1990
carol: 7/12/1990
MIM
615193
*RECORD*
*FIELD* NO
615193
*FIELD* TI
#615193 BLEEDING DISORDER, PLATELET-TYPE, 15; BDPLT15
;;MACROTHROMBOCYTOPENIA, AUTOSOMAL DOMINANT, ACTN1-RELATED
read more*FIELD* TX
A number sign (#) is used with this entry because this platelet-type
bleeding disorder (BDPLT15) is caused by heterozygous mutation in the
ACTN1 gene (102575) on chromosome 14q.
DESCRIPTION
Platelet-type bleeding disorder-15 is an autosomal dominant form of
macrothrombocytopenia. Affected individuals usually have no or only mild
bleeding tendency, such as epistaxis. Laboratory studies show decreased
numbers of large platelets and anisocytosis, but the platelets show no
in vitro functional abnormalities (summary by Kunishima et al., 2013).
CLINICAL FEATURES
Kunishima et al. (2013) reported 11 individuals from 6 unrelated
Japanese families with congenital macrothrombocytopenia. Affected
individuals had about half-normal platelet counts and a 30% increase in
platelet size. Peripheral blood smear showed anisocytosis. Electron
microscopy showed no other abnormalities. Bleeding diathesis was absent
or mild if present: only 2 individuals (15%) experienced occasional
epistaxis, and the bleeding time was within the normal limit. In vitro
studies showed no apparent defects in platelet functions, including
normal platelet aggregation, clot retraction, and platelet spreading on
glass surfaces.
INHERITANCE
The transmission pattern in the families with BDPLT15 reported by
Kunishima et al. (2013) was consistent with autosomal dominant
inheritance.
MOLECULAR GENETICS
In affected members of 6 unrelated Japanese families with autosomal
dominant platelet-type bleeding disorder-15, Kunishima et al. (2013)
identified 6 different heterozygous missense mutations in the ACTN1 gene
(102575.0001-102575.0006). Three of the mutations were identified by
exome sequencing. ACTN1 mutations were found in 5.5% of the dominant
forms of congenital macrothrombocytopenia in their cohort, and
represented the fourth most common cause of the disorder in Japanese
individuals. Expression of the mutations in Chinese hamster ovary (CHO)
cells showed that the mutant proteins caused varying degrees of
disorganization of the actin filaments, with mutant ACTN1 colocalized
with less fine, shortened actin filaments, and unbound ACTN1 coarsely
distributed within the cytoplasm. Expression of 2 of the mutations
(V105I, 102575.0001 and G32K, 102575.0002) in mouse fetal liver-derived
megakaryocytes resulted in less organization of the circumferential
actin-filament network compared to controls. The findings suggested that
ACTN1 mutations dominantly affected the actin filament assembly, likely
resulting in abnormal cytoskeletal organization. Examination of
proplatelet formation from megakaryocytes showed that the G32K and V105I
mutations did not change the rate of proplatelet formation or platelet
production, but did reduce the number of proplatelet tips and increase
the size of proplatelet tips from megakaryocytes.
*FIELD* RF
1. Kunishima, S.; Okuno, Y.; Yoshida, K.; Shiraishi, Y.; Sanada, M.;
Muramatsu, H.; Chiba, K.; Tanaka, H.; Miyazaki, K.; Sakai, M.; Ohtake,
M.; Kobayashi, R.; Iguchi, A.; Niimi, G.; Otsu, M.; Takahashi, Y.;
Miyano, S.; Saito, H.; Kojima, S.; Ogawa, S.: ACTN1 mutations cause
congenital macrothrombocytopenia. Am. J. Hum. Genet. 92: 431-438,
2013.
*FIELD* CS
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Nose];
Epistaxis (in some patients)
HEMATOLOGY:
Thrombocytopenia;
Large platelets;
Anisocytosis;
Normal platelet function
MISCELLANEOUS:
Described in 6 Japanese families;
Most patients have no bleeding abnormalities
MOLECULAR BASIS:
Caused by mutation in the alpha-1 actinin gene (ACTN1, 102565.0001)
*FIELD* CD
Cassandra L. Kniffin: 4/23/2013
*FIELD* ED
joanna: 05/03/2013
ckniffin: 4/23/2013
*FIELD* CD
Cassandra L. Kniffin: 4/23/2013
*FIELD* ED
carol: 04/24/2013
ckniffin: 4/23/2013
*RECORD*
*FIELD* NO
615193
*FIELD* TI
#615193 BLEEDING DISORDER, PLATELET-TYPE, 15; BDPLT15
;;MACROTHROMBOCYTOPENIA, AUTOSOMAL DOMINANT, ACTN1-RELATED
read more*FIELD* TX
A number sign (#) is used with this entry because this platelet-type
bleeding disorder (BDPLT15) is caused by heterozygous mutation in the
ACTN1 gene (102575) on chromosome 14q.
DESCRIPTION
Platelet-type bleeding disorder-15 is an autosomal dominant form of
macrothrombocytopenia. Affected individuals usually have no or only mild
bleeding tendency, such as epistaxis. Laboratory studies show decreased
numbers of large platelets and anisocytosis, but the platelets show no
in vitro functional abnormalities (summary by Kunishima et al., 2013).
CLINICAL FEATURES
Kunishima et al. (2013) reported 11 individuals from 6 unrelated
Japanese families with congenital macrothrombocytopenia. Affected
individuals had about half-normal platelet counts and a 30% increase in
platelet size. Peripheral blood smear showed anisocytosis. Electron
microscopy showed no other abnormalities. Bleeding diathesis was absent
or mild if present: only 2 individuals (15%) experienced occasional
epistaxis, and the bleeding time was within the normal limit. In vitro
studies showed no apparent defects in platelet functions, including
normal platelet aggregation, clot retraction, and platelet spreading on
glass surfaces.
INHERITANCE
The transmission pattern in the families with BDPLT15 reported by
Kunishima et al. (2013) was consistent with autosomal dominant
inheritance.
MOLECULAR GENETICS
In affected members of 6 unrelated Japanese families with autosomal
dominant platelet-type bleeding disorder-15, Kunishima et al. (2013)
identified 6 different heterozygous missense mutations in the ACTN1 gene
(102575.0001-102575.0006). Three of the mutations were identified by
exome sequencing. ACTN1 mutations were found in 5.5% of the dominant
forms of congenital macrothrombocytopenia in their cohort, and
represented the fourth most common cause of the disorder in Japanese
individuals. Expression of the mutations in Chinese hamster ovary (CHO)
cells showed that the mutant proteins caused varying degrees of
disorganization of the actin filaments, with mutant ACTN1 colocalized
with less fine, shortened actin filaments, and unbound ACTN1 coarsely
distributed within the cytoplasm. Expression of 2 of the mutations
(V105I, 102575.0001 and G32K, 102575.0002) in mouse fetal liver-derived
megakaryocytes resulted in less organization of the circumferential
actin-filament network compared to controls. The findings suggested that
ACTN1 mutations dominantly affected the actin filament assembly, likely
resulting in abnormal cytoskeletal organization. Examination of
proplatelet formation from megakaryocytes showed that the G32K and V105I
mutations did not change the rate of proplatelet formation or platelet
production, but did reduce the number of proplatelet tips and increase
the size of proplatelet tips from megakaryocytes.
*FIELD* RF
1. Kunishima, S.; Okuno, Y.; Yoshida, K.; Shiraishi, Y.; Sanada, M.;
Muramatsu, H.; Chiba, K.; Tanaka, H.; Miyazaki, K.; Sakai, M.; Ohtake,
M.; Kobayashi, R.; Iguchi, A.; Niimi, G.; Otsu, M.; Takahashi, Y.;
Miyano, S.; Saito, H.; Kojima, S.; Ogawa, S.: ACTN1 mutations cause
congenital macrothrombocytopenia. Am. J. Hum. Genet. 92: 431-438,
2013.
*FIELD* CS
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Nose];
Epistaxis (in some patients)
HEMATOLOGY:
Thrombocytopenia;
Large platelets;
Anisocytosis;
Normal platelet function
MISCELLANEOUS:
Described in 6 Japanese families;
Most patients have no bleeding abnormalities
MOLECULAR BASIS:
Caused by mutation in the alpha-1 actinin gene (ACTN1, 102565.0001)
*FIELD* CD
Cassandra L. Kniffin: 4/23/2013
*FIELD* ED
joanna: 05/03/2013
ckniffin: 4/23/2013
*FIELD* CD
Cassandra L. Kniffin: 4/23/2013
*FIELD* ED
carol: 04/24/2013
ckniffin: 4/23/2013