Full text data of ADD1
ADD1
(ADDA)
[Confidence: high (present in two of the MS resources)]
Alpha-adducin (Erythrocyte adducin subunit alpha)
Alpha-adducin (Erythrocyte adducin subunit alpha)
hRBCD
IPI00019901
IPI00019901 Splice isoform 1 of P35611 Alpha adducin Splice isoform 1 of P35611 Alpha adducin membrane 3 6 2 4 6 1 4 1 9 n/a 6 4 5 5 n/a 3 2 8 5 9 cytoskeleton n/a found at its expected molecular weight found at molecular weight
IPI00019901 Splice isoform 1 of P35611 Alpha adducin Splice isoform 1 of P35611 Alpha adducin membrane 3 6 2 4 6 1 4 1 9 n/a 6 4 5 5 n/a 3 2 8 5 9 cytoskeleton n/a found at its expected molecular weight found at molecular weight
Comments
Isoform P35611-3 was detected.
Isoform P35611-3 was detected.
UniProt
P35611
ID ADDA_HUMAN Reviewed; 737 AA.
AC P35611; A2A3P0; D3DVR3; D3DVR4; D3DVR5; Q13734; Q14729; Q16156;
read moreAC Q9UJB6;
DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-2000, sequence version 2.
DT 22-JAN-2014, entry version 138.
DE RecName: Full=Alpha-adducin;
DE AltName: Full=Erythrocyte adducin subunit alpha;
GN Name=ADD1; Synonyms=ADDA;
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), PROTEIN SEQUENCE OF 24-36;
RP 41-47; 516-569 AND 722-729, AND VARIANT CYS-586.
RC TISSUE=Reticulocyte;
RX PubMed=1840603; DOI=10.1083/jcb.115.3.665;
RA Joshi R.L., Gilligan D.M., Otto E., McLaughlin T., Bennett V.D.;
RT "Primary structure and domain organization of human alpha and beta
RT adducin.";
RL J. Cell Biol. 115:665-675(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND ALTERNATIVE SPLICING.
RX PubMed=7774961; DOI=10.1016/0888-7543(95)80113-Z;
RA Lin B., Nasir J., McDonald H., Graham R., Rommens J.M., Goldberg Y.P.,
RA Hayden M.R.;
RT "Genomic organization of the human alpha-adducin gene and its
RT alternately spliced isoforms.";
RL Genomics 25:93-99(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
RN [4]
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 (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 531-737 (ISOFORMS 1/3).
RX PubMed=1345173; DOI=10.1038/ng1192-223;
RA Taylor S.A., Snell R.G., Buckler A., Ambrose C., Duyao M., Church D.,
RA Lin C.S., Altherr M., Bates G.P., Groot N.;
RT "Cloning of the alpha-adducin gene from the Huntington's disease
RT candidate region of chromosome 4 by exon amplification.";
RL Nat. Genet. 2:223-227(1992).
RN [6]
RP PHOSPHORYLATION AT SER-59; SER-408; SER-436; SER-481; SER-716 AND
RP SER-726, AND PARTIAL PROTEIN SEQUENCE.
RX PubMed=8810272; DOI=10.1074/jbc.271.41.25157;
RA Matsuoka Y., Hughes C.A., Bennett V.;
RT "Adducin regulation. Definition of the calmodulin-binding domain and
RT sites of phosphorylation by protein kinases A and C.";
RL J. Biol. Chem. 271:25157-25166(1996).
RN [7]
RP PHOSPHORYLATION AT THR-445 AND THR-480, AND MUTAGENESIS OF THR-445 AND
RP THR-480.
RX PubMed=10209029; DOI=10.1083/jcb.145.2.347;
RA Fukata Y., Oshiro N., Kinoshita N., Kawano Y., Matsuoka Y.,
RA Bennett V., Matsuura Y., Kaibuchi K.;
RT "Phosphorylation of adducin by Rho-kinase plays a crucial role in cell
RT motility.";
RL J. Cell Biol. 145:347-361(1999).
RN [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-707 AND SER-710, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-358, AND MASS
RP SPECTROMETRY.
RC TISSUE=Platelet;
RX PubMed=18088087; DOI=10.1021/pr0704130;
RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT "Phosphoproteome of resting human platelets.";
RL J. Proteome Res. 7:526-534(2008).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-12; THR-331; SER-334;
RP SER-358; SER-431; SER-436 AND SER-465, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [11]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-465, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-465, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [14]
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 [15]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-12; SER-358; SER-465;
RP SER-586; SER-707; SER-710 AND SER-714, 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 [16]
RP VARIANT TRP-460.
RX PubMed=9674650; DOI=10.1161/01.HYP.32.1.138;
RA Kamitani A., Wong Z.Y., Fraser R., Davies D.L., Connor J.M., Foy C.J.,
RA Watt G.C., Harrap S.B.;
RT "Human alpha-adducin gene, blood pressure, and sodium metabolism.";
RL Hypertension 32:138-143(1998).
RN [17]
RP VARIANTS TRP-460 AND CYS-586.
RX PubMed=10391210; DOI=10.1038/10297;
RA Halushka M.K., Fan J.-B., Bentley K., Hsie L., Shen N., Weder A.,
RA Cooper R., Lipshutz R., Chakravarti A.;
RT "Patterns of single-nucleotide polymorphisms in candidate genes for
RT blood-pressure homeostasis.";
RL Nat. Genet. 22:239-247(1999).
CC -!- FUNCTION: Membrane-cytoskeleton-associated protein that promotes
CC the assembly of the spectrin-actin network. Binds to calmodulin.
CC -!- SUBUNIT: Heterodimer of an alpha and a beta subunit or an alpha
CC and a gamma subunit.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton. Cell membrane;
CC Peripheral membrane protein; Cytoplasmic side.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Comment=Additional isoforms seem to exist;
CC Name=1;
CC IsoId=P35611-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P35611-2; Sequence=VSP_000175, VSP_000176;
CC Name=3;
CC IsoId=P35611-3; Sequence=VSP_000174;
CC -!- TISSUE SPECIFICITY: Expressed in all tissues. Found in much higher
CC levels in reticulocytes than the beta subunit.
CC -!- DOMAIN: Each subunit is comprised of three regions: a NH2-terminal
CC protease-resistant globular head region, a short connecting
CC subdomain, and a protease-sensitive tail region.
CC -!- SIMILARITY: Belongs to the aldolase class II family. Adducin
CC subfamily.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAA98970.1; Type=Erroneous gene model prediction;
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DR EMBL; X58141; CAA41149.1; -; mRNA.
DR EMBL; L29296; AAB05645.1; -; Genomic_DNA.
DR EMBL; L29286; AAB05645.1; JOINED; Genomic_DNA.
DR EMBL; L29287; AAB05645.1; JOINED; Genomic_DNA.
DR EMBL; L29289; AAB05645.1; JOINED; Genomic_DNA.
DR EMBL; L29290; AAB05645.1; JOINED; Genomic_DNA.
DR EMBL; L29291; AAB05645.1; JOINED; Genomic_DNA.
DR EMBL; L29292; AAB05645.1; JOINED; Genomic_DNA.
DR EMBL; L29293; AAB05645.1; JOINED; Genomic_DNA.
DR EMBL; L29294; AAB05645.1; JOINED; Genomic_DNA.
DR EMBL; L29295; AAB05645.1; JOINED; Genomic_DNA.
DR EMBL; L29297; AAB05645.1; JOINED; Genomic_DNA.
DR EMBL; L29298; AAB05645.1; JOINED; Genomic_DNA.
DR EMBL; Z74617; CAA98970.1; ALT_SEQ; Genomic_DNA.
DR EMBL; Z68280; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL390065; CAM21299.1; -; Genomic_DNA.
DR EMBL; AL121750; CAM21299.1; JOINED; Genomic_DNA.
DR EMBL; BX465861; CAM21299.1; JOINED; Genomic_DNA.
DR EMBL; BX465861; CAM25274.1; -; Genomic_DNA.
DR EMBL; AL121750; CAM25274.1; JOINED; Genomic_DNA.
DR EMBL; AL390065; CAM25274.1; JOINED; Genomic_DNA.
DR EMBL; AL121750; CAM28232.1; -; Genomic_DNA.
DR EMBL; AL390065; CAM28232.1; JOINED; Genomic_DNA.
DR EMBL; BX465861; CAM28232.1; JOINED; Genomic_DNA.
DR EMBL; CH471131; EAW82498.1; -; Genomic_DNA.
DR EMBL; CH471131; EAW82499.1; -; Genomic_DNA.
DR EMBL; CH471131; EAW82501.1; -; Genomic_DNA.
DR EMBL; CH471131; EAW82502.1; -; Genomic_DNA.
DR EMBL; CH471131; EAW82503.1; -; Genomic_DNA.
DR EMBL; CH471131; EAW82505.1; -; Genomic_DNA.
DR EMBL; AH004561; AAB30914.2; -; mRNA.
DR PIR; S18207; S18207.
DR RefSeq; NP_001110.2; NM_001119.4.
DR RefSeq; NP_054908.2; NM_014189.3.
DR RefSeq; NP_054909.2; NM_014190.3.
DR RefSeq; NP_789771.1; NM_176801.2.
DR UniGene; Hs.183706; -.
DR DisProt; DP00240; -.
DR ProteinModelPortal; P35611; -.
DR SMR; P35611; 161-396.
DR IntAct; P35611; 10.
DR MINT; MINT-1499912; -.
DR STRING; 9606.ENSP00000264758; -.
DR PhosphoSite; P35611; -.
DR DMDM; 12644231; -.
DR PaxDb; P35611; -.
DR PRIDE; P35611; -.
DR DNASU; 118; -.
DR Ensembl; ENST00000264758; ENSP00000264758; ENSG00000087274.
DR Ensembl; ENST00000398129; ENSP00000381197; ENSG00000087274.
DR Ensembl; ENST00000446856; ENSP00000399828; ENSG00000087274.
DR GeneID; 118; -.
DR KEGG; hsa:118; -.
DR UCSC; uc003gfr.3; human.
DR CTD; 118; -.
DR GeneCards; GC04P002849; -.
DR HGNC; HGNC:243; ADD1.
DR HPA; CAB009794; -.
DR MIM; 102680; gene.
DR neXtProt; NX_P35611; -.
DR PharmGKB; PA31; -.
DR eggNOG; COG0235; -.
DR HOVERGEN; HBG004180; -.
DR OMA; WTKEDGH; -.
DR Reactome; REACT_17015; Metabolism of proteins.
DR Reactome; REACT_578; Apoptosis.
DR ChiTaRS; ADD1; human.
DR GeneWiki; ADD1; -.
DR GenomeRNAi; 118; -.
DR NextBio; 459; -.
DR PMAP-CutDB; P35611; -.
DR PRO; PR:P35611; -.
DR ArrayExpress; P35611; -.
DR Bgee; P35611; -.
DR CleanEx; HS_ADD1; -.
DR Genevestigator; P35611; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0043197; C:dendritic spine; IEA:Ensembl.
DR GO; GO:0008290; C:F-actin capping protein complex; IDA:BHF-UCL.
DR GO; GO:0005634; C:nucleus; IDA:BHF-UCL.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0014069; C:postsynaptic density; IEA:Ensembl.
DR GO; GO:0051015; F:actin filament binding; IDA:BHF-UCL.
DR GO; GO:0030507; F:spectrin binding; IDA:BHF-UCL.
DR GO; GO:0005198; F:structural molecule activity; IEA:Ensembl.
DR GO; GO:0051017; P:actin filament bundle assembly; IDA:BHF-UCL.
DR GO; GO:0006987; P:activation of signaling protein activity involved in unfolded protein response; TAS:Reactome.
DR GO; GO:0051016; P:barbed-end actin filament capping; IDA:BHF-UCL.
DR GO; GO:0000902; P:cell morphogenesis; IEA:Ensembl.
DR GO; GO:0006884; P:cell volume homeostasis; IEA:Ensembl.
DR GO; GO:0006921; P:cellular component disassembly involved in execution phase of apoptosis; TAS:Reactome.
DR GO; GO:0044267; P:cellular protein metabolic process; TAS:Reactome.
DR GO; GO:0071300; P:cellular response to retinoic acid; IEA:Ensembl.
DR GO; GO:0030218; P:erythrocyte differentiation; IEA:Ensembl.
DR GO; GO:0020027; P:hemoglobin metabolic process; IEA:Ensembl.
DR GO; GO:0048873; P:homeostasis of number of cells within a tissue; IEA:Ensembl.
DR GO; GO:0001701; P:in utero embryonic development; IEA:Ensembl.
DR GO; GO:0035264; P:multicellular organism growth; IEA:Ensembl.
DR GO; GO:0045766; P:positive regulation of angiogenesis; IEA:Ensembl.
DR GO; GO:0045807; P:positive regulation of endocytosis; IEA:Ensembl.
DR GO; GO:0032092; P:positive regulation of protein binding; IDA:BHF-UCL.
DR Gene3D; 3.40.225.10; -; 1.
DR InterPro; IPR027766; ADD1.
DR InterPro; IPR001303; Aldolase_II/adducin_N.
DR PANTHER; PTHR10672:SF4; PTHR10672:SF4; 1.
DR Pfam; PF00596; Aldolase_II; 1.
DR SMART; SM01007; Aldolase_II; 1.
DR SUPFAM; SSF53639; SSF53639; 1.
PE 1: Evidence at protein level;
KW Acetylation; Actin-binding; Alternative splicing; Calmodulin-binding;
KW Cell membrane; Complete proteome; Cytoplasm; Cytoskeleton;
KW Direct protein sequencing; Membrane; Phosphoprotein; Polymorphism;
KW Reference proteome.
FT CHAIN 1 737 Alpha-adducin.
FT /FTId=PRO_0000218530.
FT REGION 717 734 Interaction with calmodulin (Potential).
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 12 12 Phosphoserine.
FT MOD_RES 59 59 Phosphoserine; by PKA.
FT MOD_RES 331 331 Phosphothreonine.
FT MOD_RES 334 334 Phosphoserine.
FT MOD_RES 358 358 Phosphoserine.
FT MOD_RES 408 408 Phosphoserine; by PKA.
FT MOD_RES 431 431 Phosphoserine.
FT MOD_RES 436 436 Phosphoserine; by PKA.
FT MOD_RES 445 445 Phosphothreonine; by ROCK2.
FT MOD_RES 465 465 Phosphoserine.
FT MOD_RES 480 480 Phosphothreonine; by ROCK2.
FT MOD_RES 481 481 Phosphoserine; by PKA.
FT MOD_RES 586 586 Phosphoserine.
FT MOD_RES 707 707 Phosphoserine.
FT MOD_RES 710 710 Phosphoserine.
FT MOD_RES 714 714 Phosphoserine.
FT MOD_RES 716 716 Phosphoserine; by PKC.
FT MOD_RES 726 726 Phosphoserine; by PKA and PKC.
FT VAR_SEQ 471 471 K -> KVWTNITHDHVKPLLQSLSSGVCVPSCITNCL (in
FT isoform 3).
FT /FTId=VSP_000174.
FT VAR_SEQ 621 631 DLVPEPTTGDD -> GDGCAREYLLP (in isoform
FT 2).
FT /FTId=VSP_000175.
FT VAR_SEQ 632 737 Missing (in isoform 2).
FT /FTId=VSP_000176.
FT VARIANT 6 6 R -> C (in dbSNP:rs2295497).
FT /FTId=VAR_022108.
FT VARIANT 270 270 Y -> N (in dbSNP:rs4971).
FT /FTId=VAR_014863.
FT VARIANT 376 376 E -> D (in dbSNP:rs4972).
FT /FTId=VAR_014864.
FT VARIANT 460 460 G -> W (in dbSNP:rs4961).
FT /FTId=VAR_014184.
FT VARIANT 510 510 N -> I (in dbSNP:rs4962).
FT /FTId=VAR_014865.
FT VARIANT 586 586 S -> C (in dbSNP:rs4963).
FT /FTId=VAR_014185.
FT MUTAGEN 445 445 T->D: Abolishes phosphorylation by ROCK2;
FT when associated with D-480.
FT MUTAGEN 480 480 T->D: Abolishes phosphorylation by ROCK2;
FT when associated with D-445.
FT CONFLICT 606 606 A -> E (in Ref. 2; AAB05645).
SQ SEQUENCE 737 AA; 80955 MW; DF13AB30B12F20B6 CRC64;
MNGDSRAAVV TSPPPTTAPH KERYFDRVDE NNPEYLRERN MAPDLRQDFN MMEQKKRVSM
ILQSPAFCEE LESMIQEQFK KGKNPTGLLA LQQIADFMTT NVPNVYPAAP QGGMAALNMS
LGMVTPVNDL RGSDSIAYDK GEKLLRCKLA AFYRLADLFG WSQLIYNHIT TRVNSEQEHF
LIVPFGLLYS EVTASSLVKI NLQGDIVDRG STNLGVNQAG FTLHSAIYAA RPDVKCVVHI
HTPAGAAVSA MKCGLLPISP EALSLGEVAY HDYHGILVDE EEKVLIQKNL GPKSKVLILR
NHGLVSVGES VEEAFYYIHN LVVACEIQVR TLASAGGPDN LVLLNPEKYK AKSRSPGSPV
GEGTGSPPKW QIGEQEFEAL MRMLDNLGYR TGYPYRYPAL REKSKKYSDV EVPASVTGYS
FASDGDSGTC SPLRHSFQKQ QREKTRWLNS GRGDEASEEG QNGSSPKSKT KWTKEDGHRT
STSAVPNLFV PLNTNPKEVQ EMRNKIREQN LQDIKTAGPQ SQVLCGVVMD RSLVQGELVT
ASKAIIEKEY QPHVIVSTTG PNPFTTLTDR ELEEYRREVE RKQKGSEENL DEAREQKEKS
PPDQPAVPHP PPSTPIKLEE DLVPEPTTGD DSDAATFKPT LPDLSPDEPS EALGFPMLEK
EEEAHRPPSP TEAPTEASPE PAPDPAPVAE EAAPSAVEEG AAADPGSDGS PGKSPSKKKK
KFRTPSFLKK SKKKSDS
//
ID ADDA_HUMAN Reviewed; 737 AA.
AC P35611; A2A3P0; D3DVR3; D3DVR4; D3DVR5; Q13734; Q14729; Q16156;
read moreAC Q9UJB6;
DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-2000, sequence version 2.
DT 22-JAN-2014, entry version 138.
DE RecName: Full=Alpha-adducin;
DE AltName: Full=Erythrocyte adducin subunit alpha;
GN Name=ADD1; Synonyms=ADDA;
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), PROTEIN SEQUENCE OF 24-36;
RP 41-47; 516-569 AND 722-729, AND VARIANT CYS-586.
RC TISSUE=Reticulocyte;
RX PubMed=1840603; DOI=10.1083/jcb.115.3.665;
RA Joshi R.L., Gilligan D.M., Otto E., McLaughlin T., Bennett V.D.;
RT "Primary structure and domain organization of human alpha and beta
RT adducin.";
RL J. Cell Biol. 115:665-675(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND ALTERNATIVE SPLICING.
RX PubMed=7774961; DOI=10.1016/0888-7543(95)80113-Z;
RA Lin B., Nasir J., McDonald H., Graham R., Rommens J.M., Goldberg Y.P.,
RA Hayden M.R.;
RT "Genomic organization of the human alpha-adducin gene and its
RT alternately spliced isoforms.";
RL Genomics 25:93-99(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
RN [4]
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 (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 531-737 (ISOFORMS 1/3).
RX PubMed=1345173; DOI=10.1038/ng1192-223;
RA Taylor S.A., Snell R.G., Buckler A., Ambrose C., Duyao M., Church D.,
RA Lin C.S., Altherr M., Bates G.P., Groot N.;
RT "Cloning of the alpha-adducin gene from the Huntington's disease
RT candidate region of chromosome 4 by exon amplification.";
RL Nat. Genet. 2:223-227(1992).
RN [6]
RP PHOSPHORYLATION AT SER-59; SER-408; SER-436; SER-481; SER-716 AND
RP SER-726, AND PARTIAL PROTEIN SEQUENCE.
RX PubMed=8810272; DOI=10.1074/jbc.271.41.25157;
RA Matsuoka Y., Hughes C.A., Bennett V.;
RT "Adducin regulation. Definition of the calmodulin-binding domain and
RT sites of phosphorylation by protein kinases A and C.";
RL J. Biol. Chem. 271:25157-25166(1996).
RN [7]
RP PHOSPHORYLATION AT THR-445 AND THR-480, AND MUTAGENESIS OF THR-445 AND
RP THR-480.
RX PubMed=10209029; DOI=10.1083/jcb.145.2.347;
RA Fukata Y., Oshiro N., Kinoshita N., Kawano Y., Matsuoka Y.,
RA Bennett V., Matsuura Y., Kaibuchi K.;
RT "Phosphorylation of adducin by Rho-kinase plays a crucial role in cell
RT motility.";
RL J. Cell Biol. 145:347-361(1999).
RN [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-707 AND SER-710, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-358, AND MASS
RP SPECTROMETRY.
RC TISSUE=Platelet;
RX PubMed=18088087; DOI=10.1021/pr0704130;
RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT "Phosphoproteome of resting human platelets.";
RL J. Proteome Res. 7:526-534(2008).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-12; THR-331; SER-334;
RP SER-358; SER-431; SER-436 AND SER-465, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [11]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-465, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-465, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [14]
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 [15]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-12; SER-358; SER-465;
RP SER-586; SER-707; SER-710 AND SER-714, 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 [16]
RP VARIANT TRP-460.
RX PubMed=9674650; DOI=10.1161/01.HYP.32.1.138;
RA Kamitani A., Wong Z.Y., Fraser R., Davies D.L., Connor J.M., Foy C.J.,
RA Watt G.C., Harrap S.B.;
RT "Human alpha-adducin gene, blood pressure, and sodium metabolism.";
RL Hypertension 32:138-143(1998).
RN [17]
RP VARIANTS TRP-460 AND CYS-586.
RX PubMed=10391210; DOI=10.1038/10297;
RA Halushka M.K., Fan J.-B., Bentley K., Hsie L., Shen N., Weder A.,
RA Cooper R., Lipshutz R., Chakravarti A.;
RT "Patterns of single-nucleotide polymorphisms in candidate genes for
RT blood-pressure homeostasis.";
RL Nat. Genet. 22:239-247(1999).
CC -!- FUNCTION: Membrane-cytoskeleton-associated protein that promotes
CC the assembly of the spectrin-actin network. Binds to calmodulin.
CC -!- SUBUNIT: Heterodimer of an alpha and a beta subunit or an alpha
CC and a gamma subunit.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton. Cell membrane;
CC Peripheral membrane protein; Cytoplasmic side.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Comment=Additional isoforms seem to exist;
CC Name=1;
CC IsoId=P35611-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P35611-2; Sequence=VSP_000175, VSP_000176;
CC Name=3;
CC IsoId=P35611-3; Sequence=VSP_000174;
CC -!- TISSUE SPECIFICITY: Expressed in all tissues. Found in much higher
CC levels in reticulocytes than the beta subunit.
CC -!- DOMAIN: Each subunit is comprised of three regions: a NH2-terminal
CC protease-resistant globular head region, a short connecting
CC subdomain, and a protease-sensitive tail region.
CC -!- SIMILARITY: Belongs to the aldolase class II family. Adducin
CC subfamily.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAA98970.1; Type=Erroneous gene model prediction;
CC -----------------------------------------------------------------------
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DR EMBL; X58141; CAA41149.1; -; mRNA.
DR EMBL; L29296; AAB05645.1; -; Genomic_DNA.
DR EMBL; L29286; AAB05645.1; JOINED; Genomic_DNA.
DR EMBL; L29287; AAB05645.1; JOINED; Genomic_DNA.
DR EMBL; L29289; AAB05645.1; JOINED; Genomic_DNA.
DR EMBL; L29290; AAB05645.1; JOINED; Genomic_DNA.
DR EMBL; L29291; AAB05645.1; JOINED; Genomic_DNA.
DR EMBL; L29292; AAB05645.1; JOINED; Genomic_DNA.
DR EMBL; L29293; AAB05645.1; JOINED; Genomic_DNA.
DR EMBL; L29294; AAB05645.1; JOINED; Genomic_DNA.
DR EMBL; L29295; AAB05645.1; JOINED; Genomic_DNA.
DR EMBL; L29297; AAB05645.1; JOINED; Genomic_DNA.
DR EMBL; L29298; AAB05645.1; JOINED; Genomic_DNA.
DR EMBL; Z74617; CAA98970.1; ALT_SEQ; Genomic_DNA.
DR EMBL; Z68280; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL390065; CAM21299.1; -; Genomic_DNA.
DR EMBL; AL121750; CAM21299.1; JOINED; Genomic_DNA.
DR EMBL; BX465861; CAM21299.1; JOINED; Genomic_DNA.
DR EMBL; BX465861; CAM25274.1; -; Genomic_DNA.
DR EMBL; AL121750; CAM25274.1; JOINED; Genomic_DNA.
DR EMBL; AL390065; CAM25274.1; JOINED; Genomic_DNA.
DR EMBL; AL121750; CAM28232.1; -; Genomic_DNA.
DR EMBL; AL390065; CAM28232.1; JOINED; Genomic_DNA.
DR EMBL; BX465861; CAM28232.1; JOINED; Genomic_DNA.
DR EMBL; CH471131; EAW82498.1; -; Genomic_DNA.
DR EMBL; CH471131; EAW82499.1; -; Genomic_DNA.
DR EMBL; CH471131; EAW82501.1; -; Genomic_DNA.
DR EMBL; CH471131; EAW82502.1; -; Genomic_DNA.
DR EMBL; CH471131; EAW82503.1; -; Genomic_DNA.
DR EMBL; CH471131; EAW82505.1; -; Genomic_DNA.
DR EMBL; AH004561; AAB30914.2; -; mRNA.
DR PIR; S18207; S18207.
DR RefSeq; NP_001110.2; NM_001119.4.
DR RefSeq; NP_054908.2; NM_014189.3.
DR RefSeq; NP_054909.2; NM_014190.3.
DR RefSeq; NP_789771.1; NM_176801.2.
DR UniGene; Hs.183706; -.
DR DisProt; DP00240; -.
DR ProteinModelPortal; P35611; -.
DR SMR; P35611; 161-396.
DR IntAct; P35611; 10.
DR MINT; MINT-1499912; -.
DR STRING; 9606.ENSP00000264758; -.
DR PhosphoSite; P35611; -.
DR DMDM; 12644231; -.
DR PaxDb; P35611; -.
DR PRIDE; P35611; -.
DR DNASU; 118; -.
DR Ensembl; ENST00000264758; ENSP00000264758; ENSG00000087274.
DR Ensembl; ENST00000398129; ENSP00000381197; ENSG00000087274.
DR Ensembl; ENST00000446856; ENSP00000399828; ENSG00000087274.
DR GeneID; 118; -.
DR KEGG; hsa:118; -.
DR UCSC; uc003gfr.3; human.
DR CTD; 118; -.
DR GeneCards; GC04P002849; -.
DR HGNC; HGNC:243; ADD1.
DR HPA; CAB009794; -.
DR MIM; 102680; gene.
DR neXtProt; NX_P35611; -.
DR PharmGKB; PA31; -.
DR eggNOG; COG0235; -.
DR HOVERGEN; HBG004180; -.
DR OMA; WTKEDGH; -.
DR Reactome; REACT_17015; Metabolism of proteins.
DR Reactome; REACT_578; Apoptosis.
DR ChiTaRS; ADD1; human.
DR GeneWiki; ADD1; -.
DR GenomeRNAi; 118; -.
DR NextBio; 459; -.
DR PMAP-CutDB; P35611; -.
DR PRO; PR:P35611; -.
DR ArrayExpress; P35611; -.
DR Bgee; P35611; -.
DR CleanEx; HS_ADD1; -.
DR Genevestigator; P35611; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0043197; C:dendritic spine; IEA:Ensembl.
DR GO; GO:0008290; C:F-actin capping protein complex; IDA:BHF-UCL.
DR GO; GO:0005634; C:nucleus; IDA:BHF-UCL.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0014069; C:postsynaptic density; IEA:Ensembl.
DR GO; GO:0051015; F:actin filament binding; IDA:BHF-UCL.
DR GO; GO:0030507; F:spectrin binding; IDA:BHF-UCL.
DR GO; GO:0005198; F:structural molecule activity; IEA:Ensembl.
DR GO; GO:0051017; P:actin filament bundle assembly; IDA:BHF-UCL.
DR GO; GO:0006987; P:activation of signaling protein activity involved in unfolded protein response; TAS:Reactome.
DR GO; GO:0051016; P:barbed-end actin filament capping; IDA:BHF-UCL.
DR GO; GO:0000902; P:cell morphogenesis; IEA:Ensembl.
DR GO; GO:0006884; P:cell volume homeostasis; IEA:Ensembl.
DR GO; GO:0006921; P:cellular component disassembly involved in execution phase of apoptosis; TAS:Reactome.
DR GO; GO:0044267; P:cellular protein metabolic process; TAS:Reactome.
DR GO; GO:0071300; P:cellular response to retinoic acid; IEA:Ensembl.
DR GO; GO:0030218; P:erythrocyte differentiation; IEA:Ensembl.
DR GO; GO:0020027; P:hemoglobin metabolic process; IEA:Ensembl.
DR GO; GO:0048873; P:homeostasis of number of cells within a tissue; IEA:Ensembl.
DR GO; GO:0001701; P:in utero embryonic development; IEA:Ensembl.
DR GO; GO:0035264; P:multicellular organism growth; IEA:Ensembl.
DR GO; GO:0045766; P:positive regulation of angiogenesis; IEA:Ensembl.
DR GO; GO:0045807; P:positive regulation of endocytosis; IEA:Ensembl.
DR GO; GO:0032092; P:positive regulation of protein binding; IDA:BHF-UCL.
DR Gene3D; 3.40.225.10; -; 1.
DR InterPro; IPR027766; ADD1.
DR InterPro; IPR001303; Aldolase_II/adducin_N.
DR PANTHER; PTHR10672:SF4; PTHR10672:SF4; 1.
DR Pfam; PF00596; Aldolase_II; 1.
DR SMART; SM01007; Aldolase_II; 1.
DR SUPFAM; SSF53639; SSF53639; 1.
PE 1: Evidence at protein level;
KW Acetylation; Actin-binding; Alternative splicing; Calmodulin-binding;
KW Cell membrane; Complete proteome; Cytoplasm; Cytoskeleton;
KW Direct protein sequencing; Membrane; Phosphoprotein; Polymorphism;
KW Reference proteome.
FT CHAIN 1 737 Alpha-adducin.
FT /FTId=PRO_0000218530.
FT REGION 717 734 Interaction with calmodulin (Potential).
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 12 12 Phosphoserine.
FT MOD_RES 59 59 Phosphoserine; by PKA.
FT MOD_RES 331 331 Phosphothreonine.
FT MOD_RES 334 334 Phosphoserine.
FT MOD_RES 358 358 Phosphoserine.
FT MOD_RES 408 408 Phosphoserine; by PKA.
FT MOD_RES 431 431 Phosphoserine.
FT MOD_RES 436 436 Phosphoserine; by PKA.
FT MOD_RES 445 445 Phosphothreonine; by ROCK2.
FT MOD_RES 465 465 Phosphoserine.
FT MOD_RES 480 480 Phosphothreonine; by ROCK2.
FT MOD_RES 481 481 Phosphoserine; by PKA.
FT MOD_RES 586 586 Phosphoserine.
FT MOD_RES 707 707 Phosphoserine.
FT MOD_RES 710 710 Phosphoserine.
FT MOD_RES 714 714 Phosphoserine.
FT MOD_RES 716 716 Phosphoserine; by PKC.
FT MOD_RES 726 726 Phosphoserine; by PKA and PKC.
FT VAR_SEQ 471 471 K -> KVWTNITHDHVKPLLQSLSSGVCVPSCITNCL (in
FT isoform 3).
FT /FTId=VSP_000174.
FT VAR_SEQ 621 631 DLVPEPTTGDD -> GDGCAREYLLP (in isoform
FT 2).
FT /FTId=VSP_000175.
FT VAR_SEQ 632 737 Missing (in isoform 2).
FT /FTId=VSP_000176.
FT VARIANT 6 6 R -> C (in dbSNP:rs2295497).
FT /FTId=VAR_022108.
FT VARIANT 270 270 Y -> N (in dbSNP:rs4971).
FT /FTId=VAR_014863.
FT VARIANT 376 376 E -> D (in dbSNP:rs4972).
FT /FTId=VAR_014864.
FT VARIANT 460 460 G -> W (in dbSNP:rs4961).
FT /FTId=VAR_014184.
FT VARIANT 510 510 N -> I (in dbSNP:rs4962).
FT /FTId=VAR_014865.
FT VARIANT 586 586 S -> C (in dbSNP:rs4963).
FT /FTId=VAR_014185.
FT MUTAGEN 445 445 T->D: Abolishes phosphorylation by ROCK2;
FT when associated with D-480.
FT MUTAGEN 480 480 T->D: Abolishes phosphorylation by ROCK2;
FT when associated with D-445.
FT CONFLICT 606 606 A -> E (in Ref. 2; AAB05645).
SQ SEQUENCE 737 AA; 80955 MW; DF13AB30B12F20B6 CRC64;
MNGDSRAAVV TSPPPTTAPH KERYFDRVDE NNPEYLRERN MAPDLRQDFN MMEQKKRVSM
ILQSPAFCEE LESMIQEQFK KGKNPTGLLA LQQIADFMTT NVPNVYPAAP QGGMAALNMS
LGMVTPVNDL RGSDSIAYDK GEKLLRCKLA AFYRLADLFG WSQLIYNHIT TRVNSEQEHF
LIVPFGLLYS EVTASSLVKI NLQGDIVDRG STNLGVNQAG FTLHSAIYAA RPDVKCVVHI
HTPAGAAVSA MKCGLLPISP EALSLGEVAY HDYHGILVDE EEKVLIQKNL GPKSKVLILR
NHGLVSVGES VEEAFYYIHN LVVACEIQVR TLASAGGPDN LVLLNPEKYK AKSRSPGSPV
GEGTGSPPKW QIGEQEFEAL MRMLDNLGYR TGYPYRYPAL REKSKKYSDV EVPASVTGYS
FASDGDSGTC SPLRHSFQKQ QREKTRWLNS GRGDEASEEG QNGSSPKSKT KWTKEDGHRT
STSAVPNLFV PLNTNPKEVQ EMRNKIREQN LQDIKTAGPQ SQVLCGVVMD RSLVQGELVT
ASKAIIEKEY QPHVIVSTTG PNPFTTLTDR ELEEYRREVE RKQKGSEENL DEAREQKEKS
PPDQPAVPHP PPSTPIKLEE DLVPEPTTGD DSDAATFKPT LPDLSPDEPS EALGFPMLEK
EEEAHRPPSP TEAPTEASPE PAPDPAPVAE EAAPSAVEEG AAADPGSDGS PGKSPSKKKK
KFRTPSFLKK SKKKSDS
//
MIM
102680
*RECORD*
*FIELD* NO
102680
*FIELD* TI
*102680 ADDUCIN 1; ADD1
;;ADDUCIN, ALPHA
*FIELD* TX
DESCRIPTION
Adducin is a 200-kD heterodimeric protein associated with the
read moreerythrocyte membrane skeleton, which binds to Ca(2+)/calmodulin (see
114180), promotes binding of spectrin to actin, and is a substrate for
protein kinases C and A (Gardner and Bennett, 1986; Bennett et al.,
1988). The name adducin comes from the Latin 'adducere,' meaning 'to
bring together.'
CLONING
Adducin was first purified from human erythrocytes by Gardner and
Bennett (1986) and subsequently isolated from bovine brain membranes
(Bennett et al., 1988).
Joshi and Bennett (1990) investigated the structure and function of the
separate domains of alpha adducin. Joshi et al. (1991) isolated
reticulocyte cDNAs for alpha- and beta- (ADD2; 102681) adducin. The
deduced alpha-adducin protein contains 737 amino acids and shares
approximately 49% sequence identity with beta adducin, suggesting
evolution by gene duplication. Each adducin subunit has 3 distinct
domains: a 39-kD N-terminal globular protease-resistant domain,
connected by a 9-kD domain to a 33-kD C-terminal protease-sensitive tail
comprised almost entirely by hydrophilic amino acids. The head domains
of both alpha- and beta-adducin have limited sequence similarity with
the N-terminal actin-binding motif present in members of the spectrin
superfamily and actin gelation proteins. The C termini of both proteins
contain an identical 22-amino acid sequence showing similarity to the
MARCKS protein (177061). Northern blot analysis of rat tissues, K562
erythroleukemia cells, and reticulocytes demonstrated ubiquitous
expression of alpha adducin.
Goldberg et al. (1992) identified a 4-kb alpha-adducin transcript that
was abundantly expressed in the caudate nucleus, the site of major
neuronal loss in Huntington disease (HD; 143100). No sequence
alterations specific to HD were discovered in sequencing the brain
alpha-adducin cDNA from 2 HD patients and an age-matched control. Brain
cDNA from both patients and controls showed 2 alternately spliced brain
exons not previously described in erythrocyte cDNA.
In a comprehensive assay of gene expression, Gilligan et al. (1999)
showed the ubiquitous expression of alpha- and gamma-adducin (ADD3;
601568), in contrast to the restricted expression of beta-adducin.
Beta-adducin was expressed at high levels in brain and hematopoietic
tissues (bone marrow in humans, spleen in mice).
See Gilligan and Bennett (1993) for a review of adducin and the other
components of the junctional complex of the cell membrane skeleton.
MAPPING
By somatic cell hybrid analysis, Joshi et al. (1991) provisionally
assigned the ADD1 gene to chromosome 4 and the ADD2 gene to chromosome
2. Both alpha- and beta-adducin show alternative splicing; thus, there
may be several different heterodimeric or homodimeric forms of adducin,
each with a different functional specificity.
Using the technique of 'exon trapping' devised by Buckler et al. (1991),
Taylor et al. (1992) identified exons corresponding to the alpha subunit
of adducin within the 4p16.3 region where Huntington disease appeared to
be located. They mapped the ADD1 gene immediately telomeric to D4S95.
Goldberg et al. (1992) reported the isolation and cloning of cDNA for
the brain alpha-adducin gene, which they found to be located within 20
kb of D4S95.
Nasir et al. (1994) used an interspecific backcross to map the mouse
Add1 gene to chromosome 5, within the region of syntenic homology with
the short arm of human chromosome 4. Grosson et al. (1994) also mapped
the mouse Add1 gene to chromosome 5 in a continuous linkage group that
included the Huntington disease homolog.
GENE FUNCTION
Kuhlman et al. (1996) found that purified human erythrocyte adducin
completely blocked elongation and depolymerization at the fast-growing
barbed ends of actin filaments in vitro, thus functioning as a barbed
end capping protein. This barbed end capping activity required the
intact adducin molecule and was downregulated by calmodulin in the
presence of calcium. Kuhlman et al. (1996) concluded that adducin
restricts actin filament length in erythrocytes.
To investigate the molecular involvement of alpha-adducin in controlling
Na/K pump activity, Torielli et al. (2008) transfected wildtype or
mutated rat and human ADD1 into several renal cell lines and
demonstrated that the rat and human mutated forms increased Na/K pump
activity and the number of pump units; both variants
coimmunoprecipitated with the Na/K pump. The increased pump activity was
not due to changes in its basolateral location, but to an alteration of
Na/K pump residential time on the plasma membrane. Both the rat and
human mutated variants reduced constitutive Na/K pump endocytosis and
similarly affected transferrin receptor (190010) trafficking and
fluid-phase endocytosis. Alpha-adducin was also detected in clathrin
(see 118955)-coated vesicles and coimmunoprecipitated with clathrin.
Torielli et al. (2008) suggested that adducin, in addition to having
modulatory effects on actin cytoskeleton dynamics, might play a direct
role in clathrin-dependent endocytosis, and that the constitutive
reduction of Na/K pump endocytic rate induced by mutated adducin
variants might be relevant in sodium-dependent hypertension (see
145500).
MOLECULAR GENETICS
In a case-control study involving 190 patients with primary hypertension
and 126 controls, Casari et al. (1995) found an association between
essential hypertension (see 145500) and allelic markers near the
alpha-adducin locus.
Cusi et al. (1997) found significant linkage of the alpha-adducin locus
to essential hypertension and greater sensitivity to changes in sodium
balance among patients with a particular ADD1 allele, trp460
(102680.0001), suggesting that alpha adducin is associated with a
salt-sensitive form of essential hypertension.
Manunta et al. (1998) analyzed the pressure-natriuresis relationship in
108 hypertensive individuals and found that patients with a G/W or W/W
ADD1 genotype showed lower plasma renin activity and fractional
excretion of sodium as well as reduced slope of the pressure-natriuresis
relationship after sodium depletion or sodium loading compared to G/G
patients. These findings supported the hypothesis that individuals with
at least 1 ADD1 460W allele have increased renal tubular sodium
reabsorption.
Using endogenous lithium and uric acid as markers of proximal tubular
sodium reabsorption, Manunta et al. (1999) investigated the relationship
between renal sodium handling and ADD1 polymorphism in untreated
hypertensive patients and found that adducin genotype was significantly
and directly related to the fractional excretion of lithium. Manunta et
al. (1999) concluded that ADD1 represents a 'renal hypertensive gene'
that modulates the capacity of tubular epithelial cells to transport
sodium and thus affects blood pressure levels.
Allayee et al. (2001) performed a genomewide scan for blood pressure in
18 Dutch families exhibiting the common lipid disorder familial combined
hyperlipidemia (144250). They found a locus on chromosome 4 that
exhibited a significant lod score of 3.9 for systolic blood pressure. In
addition, this locus appeared to influence plasma free fatty acid levels
(lod = 2.4). After adjustment for age and gender, the lod score for
systolic blood pressure increased to 4.6, whereas the lod score for free
fatty acid levels did not change. Allayee et al. (2001) tested for an
association between 2 intragenic ADD1 polymorphisms and systolic blood
pressure in this sample and found none.
Lanzani et al. (2005) examined the association between polymorphisms in
the ADD1, ADD2, and ADD3 genes (G460W, C1797T, and IVS11+386A-G,
respectively) and ambulatory blood pressure and plasma levels of renin
activity and endogenous ouabain in 512 newly discovered and
never-treated hypertensive patients. Relative to carriers of the
wildtype (G/G) ADD1 gene, carriers of the mutant 460W allele had higher
blood pressure and lower plasma renin activity and endogenous ouabain
levels. Polymorphisms in the ADD2 and ADD3 genes taken alone were not
associated with these variables, but the blood pressure difference
between the 2 ADD1 genotypes was greatest in carriers of the ADD3 G
allele (increased by approximately 8 mm Hg; p = 0.020 to 0.006,
depending on the genetic model applied). The authors suggested that
there were epistatic effects between the ADD1 and ADD3 loci affecting
variation in blood pressure.
ANIMAL MODEL
The Milan hypertensive strain of rats develops a genetic form of renal
hypertension that, when compared to its normotensive control, shows
renal dysfunction similar to that of a subset of human patients with
primary hypertension. Bianchi et al. (1994) showed that 1 point mutation
in each of the 2 genes coding for adducin is associated with blood
pressure level in this strain of rats. The hypertensive and normal rats
differed, respectively, by the amino acids tyrosine and phenylalanine at
position 316 of the alpha subunit; at the beta-adducin locus, the
hypertensive strain was always homozygous for arginine at position 529,
while the normal strain showed either arginine or glutamine in that
position. The arg/gln heterozygotes showed lower blood pressure than any
of the homozygotes. In vitro phosphorylation studies suggested that both
of these amino acid substitutions occurred within protein kinase
recognition sites. Analysis of an F2 generation demonstrated that Y
(tyrosine) alleles segregated with a significant increment in blood
pressure. This effect was modulated by the presence of the R (arginine)
allele of the beta subunit. Bianchi et al. (1994) stated that, taken
together, these findings strongly supported a role for adducin
polymorphisms in causing variation of blood pressure in the Milan strain
of rats. In the rat, the beta- and alpha-adducin genes were said to be
located on chromosomes 4 and 14, respectively.
Tripodi et al. (1996) studied the effects of the Milan hypertensive rat
316Y and 529R mutations in Add1 and Add2, respectively, on actin
polymerization and bundling in a cell-free system and found that
double-mutated adducin exerted only a slight inhibitory effect with a
much higher final extent of polymerization compared to wildtype. Adducin
heterodimer mutated only in the beta subunit behaved as normal adducin,
whereas adducin heterodimer mutated only in the alpha subunit exhibited
an intermediate phenotype, consistent with the associated levels of
blood pressure previously described by Bianchi et al. (1994). Studies of
the actin cytoskeleton in transfected rat kidney epithelial cell lines
showed that cells overexpressing the mutated alpha-adducin chain
exhibited larger microfilament bundles and larger focal contacts with
patchy aggregates of alpha-v integrin (193210), compared to cells
overexpressing wildtype adducin, in which the microfilament bundles were
organized in a much looser texture and alpha-v integrin was present in a
diffuse punctate pattern with small focal contacts. The surface
expression of the Na-K pump alpha subunit was considerably increased in
cells overexpressing the mutated alpha-adducin chain, and Na-K pump
activity at V(max) was increased with respect to normal transfected
lines and untransfected cells. Tripodi et al. (1996) suggested that
adducin has a role in the constitutive capacity of the renal epithelia
both to transport ions and to expose adhesion molecules.
Efendiev et al. (2004) studied Milan rats carrying the hypertensive
adducin phenotype and observed higher renal tubule Na/K-ATPase activity
and found that their Na/K-ATPase molecules did not undergo endocytosis
in response to dopamine like those of normotensive rats. In the
hypertensive rats, dopamine failed to promote the interaction between
adaptins (see 601026) and the Na/K-ATPase, required for endocytosis,
because of adaptin-mu-2 subunit (602296) hyperphosphorylation.
Expression of the hypertensive rat or human variant of ADD1 into normal
renal epithelial cells recreated the hypertensive phenotype with higher
Na/K-ATPase activity, mu-2-subunit hyperphosphorylation, and impaired
Na/K-ATPase endocytosis. The authors concluded that increased renal
Na/K-ATPase activity and altered sodium reabsorption in certain forms of
hypertension could be attributed to a mutant form of adducin that
impairs the dynamic regulation of renal Na/K-ATPase endocytosis in
response to natriuretic signals.
*FIELD* AV
.0001
HYPERTENSION, SALT-SENSITIVE ESSENTIAL, SUSCEPTIBILITY TO
ADD1, GLY460TRP
Cusi et al. (1997) found a significant association between a
gly460-to-trp polymorphism (G460W) in the ADD1 gene and salt sensitivity
in patients with essential hypertension (see 145500). Patients with the
W460 allele showed greater sensitivity to changes in sodium balance, and
heterozygous hypertensive patients (G/W) showed a greater fall in mean
arterial pressure in response to 2 months' treatment with
hydrochlorothiazide, than did wildtype homozygous (G/G) hypertensive
patients. In controls in an Italian cohort, the G460 allele had a
frequency of 86.4% and the W460 allele 13.6%.
Manunta et al. (1998) analyzed the pressure-natriuresis relationship in
108 hypertensive individuals, 80 of whom were wildtype homozygous (G/G),
26 G/W heterozygous, and 2 W/W homozygous. At baseline, the G/W and W/W
patients showed lower plasma renin activity and fractional excretion of
sodium; these patients also had reduced slope of the
pressure-natriuresis relationship after sodium depletion or sodium
loading compared to G/G patients. These findings supported the
hypothesis that individuals with at least 1 ADD1 460W allele have
increased renal tubular sodium reabsorption.
Using endogenous lithium and uric acid as markers of proximal tubular
sodium reabsorption, Manunta et al. (1999) investigated the relationship
between renal sodium handling and ADD1 polymorphism in 54 untreated
hypertensive patients, 29 with the G/G genotype and 25 with the G/W
genotype. Fractional excretions of lithium and uric acid were
significantly decreased in G/W patients compared to G/G patients;
multiple regression analysis showed that adducin genotype was
significantly and directly related to the fractional excretion of
lithium. Manunta et al. (1999) concluded that ADD1 represents a 'renal
hypertensive gene' that modulates the capacity of tubular epithelial
cells to transport sodium and thus affects blood pressure levels.
*FIELD* RF
1. Allayee, H.; de Bruin, T. W. A.; Dominguez, K. M.; Cheng, L. S.-C.;
Ipp, E.; Cantor, R. M.; Krass, K. L.; Keulen, E. T. P.; Aouizerat,
B. E.; Lusis, A. J.; Rotter, J. I.: Genome scan for blood pressure
in Dutch dyslipidemic families reveals linkage to a locus on chromosome
4p. Hypertension 38: 773-778, 2001.
2. Bennett, V.; Gardner, K.; Steiner, J. P.: Brain adducin: a protein
kinase C substrate that may mediate site-directed assembly at the
spectrin-actin junction. J. Biol. Chem. 263: 5860-5869, 1988.
3. Bianchi, G.; Tripodi, G.; Casari, G.; Salardi, S.; Barber, B. R.;
Garcia, R.; Leoni, P.; Torielli, L.; Cusi, D.; Ferrandi, M.; Pinna,
L. A.; Baralle, F. E.; Ferrari, P.: Two point mutations within the
adducin genes are involved in blood pressure variation. Proc. Nat.
Acad. Sci. 91: 3999-4003, 1994.
4. Buckler, A. J.; Chang, D. D.; Graw, S. L.; Brook, J. D.; Haber,
D. A.; Sharp, P. A.; Housman, D. E.: Exon amplification: a strategy
to isolate mammalian genes based on RNA splicing. Proc. Nat. Acad.
Sci. 88: 4005-4009, 1991.
5. Casari, G.; Barlassina, C.; Cusi, D.; Zagato, L.; Muirhead, R.;
Righetti, M.; Nembri, P.; Amar, K.; Gatti, M.; Macciardi, F.; Binelli,
G.; Bianchi, G.: Association of the alpha-adducin locus with essential
hypertension. Hypertension 25: 320-326, 1995.
6. Cusi, D.; Barlassina, C.; Azzani, T.; Casari, G.; Citterio, L.;
Devoto, M.; Glorioso, N.; Lanzani, C.; Manunta, P.; Righetti, M.;
Rivera, R.; Stella, P.; Troffa, C.; Zagato, L.; Bianchi, G.: Polymorphisms
of alpha-adducin and salt sensitivity in patients with essential hypertension. Lancet 349:
1353-1357, 1997. Note: Erratum: Lancet 350: 524 only, 1997.
7. Efendiev, R.; Krmar, R. T.; Ogimoto, G.; Zwiller, J.; Tripodi,
G.; Katz, A. I.; Bianchi, G.; Pedemonte, C. H.; Bertorello, A. M.
: Hypertension-linked mutation in the adducin alpha-subunit leads
to higher AP2-mu-2 phosphorylation and impaired Na+, K+-ATPase trafficking
in response to GPCR signals and intracellular sodium. Circ. Res. 95:
1100-1108, 2004.
8. Gardner, K.; Bennett, V.: A new erythrocyte membrane-associated
protein with calmodulin binding activity: identification and purification. J.
Biol. Chem. 261: 1339-1348, 1986.
9. Gilligan, D. M.; Bennett, V.: The junctional complex of the membrane
skeleton. Seminars Hemat. 30: 74-83, 1993.
10. Gilligan, D. M.; Lozovatsky, L.; Gwynn, B.; Brugnara, C.; Mohandas,
N.; Peters, L. L.: Targeted disruption of the beta adducin gene (Add2)
causes red blood cell spherocytosis in mice. Proc. Nat. Acad. Sci. 96:
10717-10722, 1999.
11. Goldberg, Y. P.; Lin, B.-Y.; Andrew, S. E.; Nasir, J.; Graham,
R.; Glaves, M. L.; Hutchinson, G.; Theilmann, J.; Ginzinger, D. G.;
Schappert, K.; Clarke, L.; Rommens, J. M.; Hayden, M. R.: Cloning
and mapping of the alpha-adducin gene close to D4S95 and assessment
of its relationship to Huntington disease. Hum. Molec. Genet. 1:
669-675, 1992.
12. Grosson, C. L. S.; MacDonald, M. E.; Duyao, M. P.; Ambrose, C.
M.; Roffler-Tarlov, S.; Gusella, J. F.: Synteny conservation of the
Huntington's disease gene and surrounding loci on mouse chromosome
5. Mammalian Genome 5: 424-428, 1994.
13. Joshi, R.; Bennett, V.: Mapping the domain structure of human
erythrocyte adducin. J. Biol. Chem. 265: 13130-13136, 1990.
14. Joshi, R.; Gilligan, D. M.; Otto, E.; McLaughlin, T.; Bennett,
V.: Primary structure and domain organization of human alpha and
beta adducin. J. Cell Biol. 115: 665-675, 1991.
15. Kuhlman, P. A.; Hughes, C. A.; Bennett, V.; Fowler, V. M.: A
new function for adducin: calcium/calmodulin-regulated capping of
the barbed ends of actin filaments. J. Biol. Chem. 271: 7986-7991,
1996.
16. Lanzani, C.; Citterio, L.; Jankaricova, M.; Sciarrone, M. T.;
Barlassina, C.; Fattori, S.; Messaggio, E.; Di Serio, C.; Zagato,
L.; Cusi, D.; Hamlyn, J. M.; Stella, A.; Bianchi, G.; Manunta, P.
: Role of the adducin family genes in human essential hypertension. J.
Hypertension 23: 543-549, 2005.
17. Manunta, P.; Burnier, M.; D'Amico, M.; Buzzi, L.; Maillard, M.;
Barlassina, C.; Lanella, G.; Cusi, D.; Bianchi, G.: Adducin polymorphism
affects renal proximal tubule reabsorption in hypertension. Hypertension 33:
694-697, 1999.
18. Manunta, P.; Cusi, D.; Barlassina, C.; Righetti, M.; Lanzani,
C.; D'Amico, M.; Buzzi, L.; Citterio, L.; Stella, P.; Rivera, R.;
Bianchi, G.: Alpha-adducin polymorphisms and renal sodium handling
in essential hypertensive patients. Kidney Int. 53: 1471-1478, 1998.
19. Nasir, J.; Lin, B.; Bucan, M.; Koizumi, T.; Nadeau, J. H.; Hayden,
M. R.: The murine homologues of the Huntington disease gene (Hdh)
and the alpha-adducin gene (Add1) map to mouse chromosome 5 within
a region of conserved synteny with human chromosome 4p16.3. Genomics 22:
198-201, 1994.
20. Taylor, S. A. M.; Snell, R. G.; Buckler, A.; Ambrose, C.; Duyao,
M.; Church, D.; Lin, C. S.; Altherr, M.; Bates, G. P.; Groot, N.;
Barnes, G.; Shaw, D. J.; Lehrach, H.; Wasmuth, J. J.; Harper, P. S.;
Housman, D. E.; MacDonald, M. E.; Gusella, J. F.: Cloning of the
alpha-adducin gene from the Huntington's disease candidate region
of chromosome 4 by exon amplification. Nature Genet. 2: 223-227,
1992.
21. Torielli, L.; Tivodar, S.; Montella, R. C.; Iacone, R.; Padoani,
G.; Tarsini, P.; Russo, O.; Sarnataro, D.; Strazzullo, P.; Ferrari,
P.; Bianchi, G.; Zurzolo, C.: Alpha-adducin mutations increase Na/K
pump activity in renal cells by affecting constitutive endocytosis:
implications for tubular Na reabsorption. Am. J. Physiol. Renal Physiol. 295:
F478-F487, 2008.
22. Tripodi, G.; Valtorta, F.; Torielli, L.; Chieregatti, E.; Salardi,
S.; Trusolino, L.; Menegon, A.; Ferrari, P.; Marchisio, P.-C.; Bianchi,
G.: Hypertension-associated point mutations in the adducin alpha
and beta subunits affect actin cytoskeleton and ion transport. J.
Clin. Invest. 97: 2815-2822, 1996.
*FIELD* CN
Patricia A. Hartz - updated: 4/10/2009
Marla J. F. O'Neill - updated: 12/2/2008
Victor A. McKusick - updated: 3/8/2005
Victor A. McKusick - updated: 1/4/2002
Victor A. McKusick - updated: 11/8/1999
*FIELD* CD
Victor A. McKusick: 12/9/1991
*FIELD* ED
terry: 08/31/2012
mgross: 4/10/2009
terry: 4/10/2009
terry: 12/23/2008
carol: 12/8/2008
carol: 12/2/2008
wwang: 3/10/2005
wwang: 3/9/2005
terry: 3/8/2005
terry: 3/6/2002
carol: 1/11/2002
mcapotos: 1/8/2002
terry: 1/4/2002
mgross: 11/8/1999
carol: 2/18/1999
mark: 5/7/1997
terry: 5/2/1997
terry: 8/26/1994
jason: 7/19/1994
carol: 6/1/1994
carol: 3/20/1993
carol: 2/18/1993
carol: 2/2/1993
*RECORD*
*FIELD* NO
102680
*FIELD* TI
*102680 ADDUCIN 1; ADD1
;;ADDUCIN, ALPHA
*FIELD* TX
DESCRIPTION
Adducin is a 200-kD heterodimeric protein associated with the
read moreerythrocyte membrane skeleton, which binds to Ca(2+)/calmodulin (see
114180), promotes binding of spectrin to actin, and is a substrate for
protein kinases C and A (Gardner and Bennett, 1986; Bennett et al.,
1988). The name adducin comes from the Latin 'adducere,' meaning 'to
bring together.'
CLONING
Adducin was first purified from human erythrocytes by Gardner and
Bennett (1986) and subsequently isolated from bovine brain membranes
(Bennett et al., 1988).
Joshi and Bennett (1990) investigated the structure and function of the
separate domains of alpha adducin. Joshi et al. (1991) isolated
reticulocyte cDNAs for alpha- and beta- (ADD2; 102681) adducin. The
deduced alpha-adducin protein contains 737 amino acids and shares
approximately 49% sequence identity with beta adducin, suggesting
evolution by gene duplication. Each adducin subunit has 3 distinct
domains: a 39-kD N-terminal globular protease-resistant domain,
connected by a 9-kD domain to a 33-kD C-terminal protease-sensitive tail
comprised almost entirely by hydrophilic amino acids. The head domains
of both alpha- and beta-adducin have limited sequence similarity with
the N-terminal actin-binding motif present in members of the spectrin
superfamily and actin gelation proteins. The C termini of both proteins
contain an identical 22-amino acid sequence showing similarity to the
MARCKS protein (177061). Northern blot analysis of rat tissues, K562
erythroleukemia cells, and reticulocytes demonstrated ubiquitous
expression of alpha adducin.
Goldberg et al. (1992) identified a 4-kb alpha-adducin transcript that
was abundantly expressed in the caudate nucleus, the site of major
neuronal loss in Huntington disease (HD; 143100). No sequence
alterations specific to HD were discovered in sequencing the brain
alpha-adducin cDNA from 2 HD patients and an age-matched control. Brain
cDNA from both patients and controls showed 2 alternately spliced brain
exons not previously described in erythrocyte cDNA.
In a comprehensive assay of gene expression, Gilligan et al. (1999)
showed the ubiquitous expression of alpha- and gamma-adducin (ADD3;
601568), in contrast to the restricted expression of beta-adducin.
Beta-adducin was expressed at high levels in brain and hematopoietic
tissues (bone marrow in humans, spleen in mice).
See Gilligan and Bennett (1993) for a review of adducin and the other
components of the junctional complex of the cell membrane skeleton.
MAPPING
By somatic cell hybrid analysis, Joshi et al. (1991) provisionally
assigned the ADD1 gene to chromosome 4 and the ADD2 gene to chromosome
2. Both alpha- and beta-adducin show alternative splicing; thus, there
may be several different heterodimeric or homodimeric forms of adducin,
each with a different functional specificity.
Using the technique of 'exon trapping' devised by Buckler et al. (1991),
Taylor et al. (1992) identified exons corresponding to the alpha subunit
of adducin within the 4p16.3 region where Huntington disease appeared to
be located. They mapped the ADD1 gene immediately telomeric to D4S95.
Goldberg et al. (1992) reported the isolation and cloning of cDNA for
the brain alpha-adducin gene, which they found to be located within 20
kb of D4S95.
Nasir et al. (1994) used an interspecific backcross to map the mouse
Add1 gene to chromosome 5, within the region of syntenic homology with
the short arm of human chromosome 4. Grosson et al. (1994) also mapped
the mouse Add1 gene to chromosome 5 in a continuous linkage group that
included the Huntington disease homolog.
GENE FUNCTION
Kuhlman et al. (1996) found that purified human erythrocyte adducin
completely blocked elongation and depolymerization at the fast-growing
barbed ends of actin filaments in vitro, thus functioning as a barbed
end capping protein. This barbed end capping activity required the
intact adducin molecule and was downregulated by calmodulin in the
presence of calcium. Kuhlman et al. (1996) concluded that adducin
restricts actin filament length in erythrocytes.
To investigate the molecular involvement of alpha-adducin in controlling
Na/K pump activity, Torielli et al. (2008) transfected wildtype or
mutated rat and human ADD1 into several renal cell lines and
demonstrated that the rat and human mutated forms increased Na/K pump
activity and the number of pump units; both variants
coimmunoprecipitated with the Na/K pump. The increased pump activity was
not due to changes in its basolateral location, but to an alteration of
Na/K pump residential time on the plasma membrane. Both the rat and
human mutated variants reduced constitutive Na/K pump endocytosis and
similarly affected transferrin receptor (190010) trafficking and
fluid-phase endocytosis. Alpha-adducin was also detected in clathrin
(see 118955)-coated vesicles and coimmunoprecipitated with clathrin.
Torielli et al. (2008) suggested that adducin, in addition to having
modulatory effects on actin cytoskeleton dynamics, might play a direct
role in clathrin-dependent endocytosis, and that the constitutive
reduction of Na/K pump endocytic rate induced by mutated adducin
variants might be relevant in sodium-dependent hypertension (see
145500).
MOLECULAR GENETICS
In a case-control study involving 190 patients with primary hypertension
and 126 controls, Casari et al. (1995) found an association between
essential hypertension (see 145500) and allelic markers near the
alpha-adducin locus.
Cusi et al. (1997) found significant linkage of the alpha-adducin locus
to essential hypertension and greater sensitivity to changes in sodium
balance among patients with a particular ADD1 allele, trp460
(102680.0001), suggesting that alpha adducin is associated with a
salt-sensitive form of essential hypertension.
Manunta et al. (1998) analyzed the pressure-natriuresis relationship in
108 hypertensive individuals and found that patients with a G/W or W/W
ADD1 genotype showed lower plasma renin activity and fractional
excretion of sodium as well as reduced slope of the pressure-natriuresis
relationship after sodium depletion or sodium loading compared to G/G
patients. These findings supported the hypothesis that individuals with
at least 1 ADD1 460W allele have increased renal tubular sodium
reabsorption.
Using endogenous lithium and uric acid as markers of proximal tubular
sodium reabsorption, Manunta et al. (1999) investigated the relationship
between renal sodium handling and ADD1 polymorphism in untreated
hypertensive patients and found that adducin genotype was significantly
and directly related to the fractional excretion of lithium. Manunta et
al. (1999) concluded that ADD1 represents a 'renal hypertensive gene'
that modulates the capacity of tubular epithelial cells to transport
sodium and thus affects blood pressure levels.
Allayee et al. (2001) performed a genomewide scan for blood pressure in
18 Dutch families exhibiting the common lipid disorder familial combined
hyperlipidemia (144250). They found a locus on chromosome 4 that
exhibited a significant lod score of 3.9 for systolic blood pressure. In
addition, this locus appeared to influence plasma free fatty acid levels
(lod = 2.4). After adjustment for age and gender, the lod score for
systolic blood pressure increased to 4.6, whereas the lod score for free
fatty acid levels did not change. Allayee et al. (2001) tested for an
association between 2 intragenic ADD1 polymorphisms and systolic blood
pressure in this sample and found none.
Lanzani et al. (2005) examined the association between polymorphisms in
the ADD1, ADD2, and ADD3 genes (G460W, C1797T, and IVS11+386A-G,
respectively) and ambulatory blood pressure and plasma levels of renin
activity and endogenous ouabain in 512 newly discovered and
never-treated hypertensive patients. Relative to carriers of the
wildtype (G/G) ADD1 gene, carriers of the mutant 460W allele had higher
blood pressure and lower plasma renin activity and endogenous ouabain
levels. Polymorphisms in the ADD2 and ADD3 genes taken alone were not
associated with these variables, but the blood pressure difference
between the 2 ADD1 genotypes was greatest in carriers of the ADD3 G
allele (increased by approximately 8 mm Hg; p = 0.020 to 0.006,
depending on the genetic model applied). The authors suggested that
there were epistatic effects between the ADD1 and ADD3 loci affecting
variation in blood pressure.
ANIMAL MODEL
The Milan hypertensive strain of rats develops a genetic form of renal
hypertension that, when compared to its normotensive control, shows
renal dysfunction similar to that of a subset of human patients with
primary hypertension. Bianchi et al. (1994) showed that 1 point mutation
in each of the 2 genes coding for adducin is associated with blood
pressure level in this strain of rats. The hypertensive and normal rats
differed, respectively, by the amino acids tyrosine and phenylalanine at
position 316 of the alpha subunit; at the beta-adducin locus, the
hypertensive strain was always homozygous for arginine at position 529,
while the normal strain showed either arginine or glutamine in that
position. The arg/gln heterozygotes showed lower blood pressure than any
of the homozygotes. In vitro phosphorylation studies suggested that both
of these amino acid substitutions occurred within protein kinase
recognition sites. Analysis of an F2 generation demonstrated that Y
(tyrosine) alleles segregated with a significant increment in blood
pressure. This effect was modulated by the presence of the R (arginine)
allele of the beta subunit. Bianchi et al. (1994) stated that, taken
together, these findings strongly supported a role for adducin
polymorphisms in causing variation of blood pressure in the Milan strain
of rats. In the rat, the beta- and alpha-adducin genes were said to be
located on chromosomes 4 and 14, respectively.
Tripodi et al. (1996) studied the effects of the Milan hypertensive rat
316Y and 529R mutations in Add1 and Add2, respectively, on actin
polymerization and bundling in a cell-free system and found that
double-mutated adducin exerted only a slight inhibitory effect with a
much higher final extent of polymerization compared to wildtype. Adducin
heterodimer mutated only in the beta subunit behaved as normal adducin,
whereas adducin heterodimer mutated only in the alpha subunit exhibited
an intermediate phenotype, consistent with the associated levels of
blood pressure previously described by Bianchi et al. (1994). Studies of
the actin cytoskeleton in transfected rat kidney epithelial cell lines
showed that cells overexpressing the mutated alpha-adducin chain
exhibited larger microfilament bundles and larger focal contacts with
patchy aggregates of alpha-v integrin (193210), compared to cells
overexpressing wildtype adducin, in which the microfilament bundles were
organized in a much looser texture and alpha-v integrin was present in a
diffuse punctate pattern with small focal contacts. The surface
expression of the Na-K pump alpha subunit was considerably increased in
cells overexpressing the mutated alpha-adducin chain, and Na-K pump
activity at V(max) was increased with respect to normal transfected
lines and untransfected cells. Tripodi et al. (1996) suggested that
adducin has a role in the constitutive capacity of the renal epithelia
both to transport ions and to expose adhesion molecules.
Efendiev et al. (2004) studied Milan rats carrying the hypertensive
adducin phenotype and observed higher renal tubule Na/K-ATPase activity
and found that their Na/K-ATPase molecules did not undergo endocytosis
in response to dopamine like those of normotensive rats. In the
hypertensive rats, dopamine failed to promote the interaction between
adaptins (see 601026) and the Na/K-ATPase, required for endocytosis,
because of adaptin-mu-2 subunit (602296) hyperphosphorylation.
Expression of the hypertensive rat or human variant of ADD1 into normal
renal epithelial cells recreated the hypertensive phenotype with higher
Na/K-ATPase activity, mu-2-subunit hyperphosphorylation, and impaired
Na/K-ATPase endocytosis. The authors concluded that increased renal
Na/K-ATPase activity and altered sodium reabsorption in certain forms of
hypertension could be attributed to a mutant form of adducin that
impairs the dynamic regulation of renal Na/K-ATPase endocytosis in
response to natriuretic signals.
*FIELD* AV
.0001
HYPERTENSION, SALT-SENSITIVE ESSENTIAL, SUSCEPTIBILITY TO
ADD1, GLY460TRP
Cusi et al. (1997) found a significant association between a
gly460-to-trp polymorphism (G460W) in the ADD1 gene and salt sensitivity
in patients with essential hypertension (see 145500). Patients with the
W460 allele showed greater sensitivity to changes in sodium balance, and
heterozygous hypertensive patients (G/W) showed a greater fall in mean
arterial pressure in response to 2 months' treatment with
hydrochlorothiazide, than did wildtype homozygous (G/G) hypertensive
patients. In controls in an Italian cohort, the G460 allele had a
frequency of 86.4% and the W460 allele 13.6%.
Manunta et al. (1998) analyzed the pressure-natriuresis relationship in
108 hypertensive individuals, 80 of whom were wildtype homozygous (G/G),
26 G/W heterozygous, and 2 W/W homozygous. At baseline, the G/W and W/W
patients showed lower plasma renin activity and fractional excretion of
sodium; these patients also had reduced slope of the
pressure-natriuresis relationship after sodium depletion or sodium
loading compared to G/G patients. These findings supported the
hypothesis that individuals with at least 1 ADD1 460W allele have
increased renal tubular sodium reabsorption.
Using endogenous lithium and uric acid as markers of proximal tubular
sodium reabsorption, Manunta et al. (1999) investigated the relationship
between renal sodium handling and ADD1 polymorphism in 54 untreated
hypertensive patients, 29 with the G/G genotype and 25 with the G/W
genotype. Fractional excretions of lithium and uric acid were
significantly decreased in G/W patients compared to G/G patients;
multiple regression analysis showed that adducin genotype was
significantly and directly related to the fractional excretion of
lithium. Manunta et al. (1999) concluded that ADD1 represents a 'renal
hypertensive gene' that modulates the capacity of tubular epithelial
cells to transport sodium and thus affects blood pressure levels.
*FIELD* RF
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*FIELD* CN
Patricia A. Hartz - updated: 4/10/2009
Marla J. F. O'Neill - updated: 12/2/2008
Victor A. McKusick - updated: 3/8/2005
Victor A. McKusick - updated: 1/4/2002
Victor A. McKusick - updated: 11/8/1999
*FIELD* CD
Victor A. McKusick: 12/9/1991
*FIELD* ED
terry: 08/31/2012
mgross: 4/10/2009
terry: 4/10/2009
terry: 12/23/2008
carol: 12/8/2008
carol: 12/2/2008
wwang: 3/10/2005
wwang: 3/9/2005
terry: 3/8/2005
terry: 3/6/2002
carol: 1/11/2002
mcapotos: 1/8/2002
terry: 1/4/2002
mgross: 11/8/1999
carol: 2/18/1999
mark: 5/7/1997
terry: 5/2/1997
terry: 8/26/1994
jason: 7/19/1994
carol: 6/1/1994
carol: 3/20/1993
carol: 2/18/1993
carol: 2/2/1993