Full text data of PACS1
PACS1
(KIAA1175)
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Phosphofurin acidic cluster sorting protein 1; PACS-1
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Phosphofurin acidic cluster sorting protein 1; PACS-1
Note: presumably soluble (membrane word is not in UniProt keywords or features)
hRBCD
IPI00376229
IPI00376229 Splice Isoform 1 Of Phosphofurin acidic cluster sorting protein 1 Splice Isoform 1 Of Phosphofurin acidic cluster sorting protein 1 membrane n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 1 n/a n/a membrane bound SEPPVSEQLDVAGR (identified at least 3 times) found at its expected molecular weight found at molecular weight
IPI00376229 Splice Isoform 1 Of Phosphofurin acidic cluster sorting protein 1 Splice Isoform 1 Of Phosphofurin acidic cluster sorting protein 1 membrane n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 1 n/a n/a membrane bound SEPPVSEQLDVAGR (identified at least 3 times) found at its expected molecular weight found at molecular weight
UniProt
Q6VY07
ID PACS1_HUMAN Reviewed; 963 AA.
AC Q6VY07; Q6PJY6; Q6PKB6; Q7Z590; Q7Z5W4; Q8N8K6; Q96MW0; Q9NW92;
read moreAC Q9ULP5;
DT 13-SEP-2004, integrated into UniProtKB/Swiss-Prot.
DT 13-SEP-2004, sequence version 2.
DT 22-JAN-2014, entry version 95.
DE RecName: Full=Phosphofurin acidic cluster sorting protein 1;
DE Short=PACS-1;
GN Name=PACS1; Synonyms=KIAA1175;
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).
RA Wan L., Xiang Y., Simmen T., Thomas G.;
RT "Human PACS-1, a endosome-TGN sorting connector.";
RL Submitted (JUN-2003) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Embryo, and Fetal 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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain, Kidney, and Uterus;
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 323-963 (ISOFORM 1).
RC TISSUE=Brain;
RX PubMed=10574461; DOI=10.1093/dnares/6.5.329;
RA Hirosawa M., Nagase T., Ishikawa K., Kikuno R., Nomura N., Ohara O.;
RT "Characterization of cDNA clones selected by the GeneMark analysis
RT from size-fractionated cDNA libraries from human brain.";
RL DNA Res. 6:329-336(1999).
RN [5]
RP FUNCTION.
RX PubMed=11331585; DOI=10.1093/emboj/20.9.2191;
RA Crump C.M., Xiang Y., Thomas L., Gu F., Austin C., Tooze S.A.,
RA Thomas G.;
RT "PACS-1 binding to adaptors is required for acidic cluster motif-
RT mediated protein traffic.";
RL EMBO J. 20:2191-2201(2001).
RN [6]
RP INTERACTION WITH HIV-1 NEF.
RX PubMed=10707087; DOI=10.1038/35004038;
RA Piguet V., Wan L., Borel C., Mangasarian A., Demaurex N., Thomas G.,
RA Trono D.;
RT "HIV-1 Nef protein binds to the cellular protein PACS-1 to
RT downregulate class I major histocompatibility complexes.";
RL Nat. Cell Biol. 2:163-167(2000).
RN [7]
RP INTERACTION WITH HIV-1 NEF.
RX PubMed=12526811; DOI=10.1016/S0092-8674(02)01162-5;
RA Blagoveshchenskaya A.D., Thomas L., Feliciangeli S.F., Hung C.-H.,
RA Thomas G.;
RT "HIV-1 Nef downregulates MHC-I by a PACS-1- and PI3K-regulated ARF6
RT endocytic pathway.";
RL Cell 111:853-866(2002).
RN [8]
RP INTERACTION WITH NPHP1.
RX PubMed=16308564; DOI=10.1038/sj.emboj.7600885;
RA Schermer B., Hoepker K., Omran H., Ghenoiu C., Fliegauf M., Fekete A.,
RA Horvath J., Koettgen M., Hackl M., Zschiedrich S., Huber T.B.,
RA Kramer-Zucker A., Zentgraf H., Blaukat A., Walz G., Benzing T.;
RT "Phosphorylation by casein kinase 2 induces PACS-1 binding of
RT nephrocystin and targeting to cilia.";
RL EMBO J. 24:4415-4424(2005).
RN [9]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Embryonic kidney;
RX PubMed=17525332; DOI=10.1126/science.1140321;
RA Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III,
RA Hurov K.E., Luo J., Bakalarski C.E., Zhao Z., Solimini N.,
RA Lerenthal Y., Shiloh Y., Gygi S.P., Elledge S.J.;
RT "ATM and ATR substrate analysis reveals extensive protein networks
RT responsive to DNA damage.";
RL Science 316:1160-1166(2007).
RN [10]
RP INTERACTION WITH HIV-1 NEF.
RX PubMed=18296443; DOI=10.1074/jbc.M707572200;
RA Atkins K.M., Thomas L., Youker R.T., Harriff M.J., Pissani F., You H.,
RA Thomas G.;
RT "HIV-1 Nef binds PACS-2 to assemble a multikinase cascade that
RT triggers major histocompatibility complex class I (MHC-I) down-
RT regulation: analysis using short interfering RNA and knock-out mice.";
RL J. Biol. Chem. 283:11772-11784(2008).
RN [11]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-379; SER-430; THR-504;
RP SER-529 AND SER-534, 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 [13]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
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 [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [15]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-531, AND MASS
RP 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 [17]
RP VARIANT MRD17 TRP-203.
RX PubMed=23159249; DOI=10.1016/j.ajhg.2012.10.013;
RA Schuurs-Hoeijmakers J.H., Oh E.C., Vissers L.E., Swinkels M.E.,
RA Gilissen C., Willemsen M.A., Holvoet M., Steehouwer M., Veltman J.A.,
RA de Vries B.B., van Bokhoven H., de Brouwer A.P., Katsanis N.,
RA Devriendt K., Brunner H.G.;
RT "Recurrent de novo mutations in PACS1 cause defective cranial-neural-
RT crest migration and define a recognizable intellectual-disability
RT syndrome.";
RL Am. J. Hum. Genet. 91:1122-1127(2012).
CC -!- FUNCTION: Coat protein that is involved in the localization of
CC trans-Golgi network (TGN) membrane proteins that contain acidic
CC cluster sorting motifs. Controls the endosome-to-Golgi trafficking
CC of furin and mannose-6-phosphate receptor by connecting the
CC acidic-cluster-containing cytoplasmic domain of these molecules
CC with the adapter-protein complex-1 (AP-1) of endosomal clathrin-
CC coated membrane pits. Involved in HIV-1 nef-mediated removal of
CC MHC-I from the cell surface to the TGN.
CC -!- SUBUNIT: Interacts with HIV-1 Nef. Associates with AP-1 and AP-3
CC but not with AP-2 complexes. Interacts with NPHP1; the interaction
CC is dependent of NPHP1 phosphorylation by CK2.
CC -!- INTERACTION:
CC P67870:CSNK2B; NbExp=3; IntAct=EBI-2555014, EBI-348169;
CC Q9NZ52:GGA3; NbExp=5; IntAct=EBI-2555014, EBI-447404;
CC P11717:IGF2R; NbExp=2; IntAct=EBI-2555014, EBI-1048580;
CC -!- SUBCELLULAR LOCATION: Golgi apparatus, trans-Golgi network (By
CC similarity). Note=Localizes in the perinuclear region, probably
CC the TGN (By similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q6VY07-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q6VY07-2; Sequence=VSP_011557;
CC Note=No experimental confirmation available;
CC -!- DISEASE: Mental retardation, autosomal dominant 17 (MRD17)
CC [MIM:615009]: A disorder characterized by significantly below
CC average general intellectual functioning associated with
CC impairments in adaptive behavior and manifested during the
CC developmental period. MRD17 patients have intellectual disability
CC in combination with distinct craniofacial features and genital
CC abnormalities. Note=The disease is caused by mutations affecting
CC the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the PACS family.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH09936.1; Type=Erroneous initiation; Note=Translation N-terminally shortened;
CC Sequence=BAB71164.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
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DR EMBL; AY320283; AAQ67682.1; -; mRNA.
DR EMBL; AK001071; BAA91491.1; -; mRNA.
DR EMBL; AK056361; BAB71164.1; ALT_INIT; mRNA.
DR EMBL; AK096644; BAC04831.1; -; mRNA.
DR EMBL; BC003173; AAH03173.1; -; mRNA.
DR EMBL; BC010096; AAH10096.1; -; mRNA.
DR EMBL; BC009936; AAH09936.1; ALT_INIT; mRNA.
DR EMBL; BC052577; AAH52577.1; -; mRNA.
DR EMBL; BC055288; AAH55288.1; -; mRNA.
DR EMBL; AB033001; BAA86489.1; -; mRNA.
DR RefSeq; NP_060496.2; NM_018026.3.
DR UniGene; Hs.644326; -.
DR ProteinModelPortal; Q6VY07; -.
DR IntAct; Q6VY07; 8.
DR MINT; MINT-3372090; -.
DR PhosphoSite; Q6VY07; -.
DR DMDM; 52000804; -.
DR PaxDb; Q6VY07; -.
DR PRIDE; Q6VY07; -.
DR Ensembl; ENST00000320580; ENSP00000316454; ENSG00000175115.
DR GeneID; 55690; -.
DR KEGG; hsa:55690; -.
DR UCSC; uc001oha.2; human.
DR CTD; 55690; -.
DR GeneCards; GC11P065837; -.
DR HGNC; HGNC:30032; PACS1.
DR HPA; HPA038914; -.
DR MIM; 607492; gene.
DR MIM; 615009; phenotype.
DR neXtProt; NX_Q6VY07; -.
DR Orphanet; 329224; Intellectual deficit - craniofacial dysmorphism - cryptorchidism.
DR PharmGKB; PA134989529; -.
DR eggNOG; NOG279176; -.
DR HOVERGEN; HBG053488; -.
DR InParanoid; Q6VY07; -.
DR OMA; TPAPVQM; -.
DR OrthoDB; EOG7VHSX0; -.
DR PhylomeDB; Q6VY07; -.
DR Reactome; REACT_116125; Disease.
DR ChiTaRS; PACS1; human.
DR GeneWiki; PACS1; -.
DR GenomeRNAi; 55690; -.
DR NextBio; 60497; -.
DR PRO; PR:Q6VY07; -.
DR ArrayExpress; Q6VY07; -.
DR Bgee; Q6VY07; -.
DR Genevestigator; Q6VY07; -.
DR GO; GO:0030137; C:COPI-coated vesicle; IEA:Ensembl.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR GO; GO:0000042; P:protein targeting to Golgi; IEA:Ensembl.
DR GO; GO:0072661; P:protein targeting to plasma membrane; IMP:BHF-UCL.
DR GO; GO:0050690; P:regulation of defense response to virus by virus; TAS:Reactome.
DR GO; GO:0016032; P:viral process; TAS:Reactome.
DR InterPro; IPR019381; Phosphofurin_acidic_CS-1.
DR Pfam; PF10254; Pacs-1; 1.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; Coiled coil; Complete proteome;
KW Disease mutation; Golgi apparatus; Host-virus interaction;
KW Mental retardation; Phosphoprotein; Polymorphism; Reference proteome.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 963 Phosphofurin acidic cluster sorting
FT protein 1.
FT /FTId=PRO_0000058171.
FT REGION 168 175 Involved in binding to AP-1.
FT COILED 353 377 Potential.
FT COMPBIAS 5 44 Gly-rich.
FT COMPBIAS 35 40 Poly-Gln.
FT COMPBIAS 55 84 Ser-rich.
FT COMPBIAS 62 65 Poly-Ala.
FT COMPBIAS 112 115 Poly-Ser.
FT COMPBIAS 279 283 Poly-Glu.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 379 379 Phosphoserine.
FT MOD_RES 430 430 Phosphoserine.
FT MOD_RES 504 504 Phosphothreonine.
FT MOD_RES 529 529 Phosphoserine.
FT MOD_RES 531 531 Phosphoserine.
FT MOD_RES 534 534 Phosphoserine.
FT VAR_SEQ 917 963 AKQQQTMLRVSIDGVEWSDIKFFQLAAQWPTHVKHFPVGLF
FT SGSKAT -> SPSLGPSLGPDPSSQPGFPPAGSFPPCHLPL
FT TNPGSEPLIPDRPCSQEWLRTQGPSPALCTPQPGHLRPTAP
FT LELFSCPLTPSQKFLHRTSF (in isoform 2).
FT /FTId=VSP_011557.
FT VARIANT 203 203 R -> W (in MRD17).
FT /FTId=VAR_069534.
FT VARIANT 302 302 F -> L (in dbSNP:rs12798852).
FT /FTId=VAR_053797.
FT CONFLICT 171 220 Missing (in Ref. 2; BAC04831).
FT CONFLICT 649 649 K -> M (in Ref. 2; BAA91491).
FT CONFLICT 771 771 P -> S (in Ref. 2; BAC04831).
FT CONFLICT 803 803 S -> N (in Ref. 1; AAQ67682).
FT CONFLICT 882 882 K -> L (in Ref. 1; AAQ67682).
SQ SEQUENCE 963 AA; 104898 MW; 0F6B2CA24F7CD567 CRC64;
MAERGGAGGG PGGAGGGSGQ RGSGVAQSPQ QPPPQQQQQQ PPQQPTPPKL AQATSSSSST
SAAAASSSSS STSTSMAVAV ASGSAPPGGP GPGRTPAPVQ MNLYATWEVD RSSSSCVPRL
FSLTLKKLVM LKEMDKDLNS VVIAVKLQGS KRILRSNEIV LPASGLVETE LQLTFSLQYP
HFLKRDANKL QIMLQRRKRY KNRTILGYKT LAVGLINMAE VMQHPNEGAL VLGLHSNVKD
VSVPVAEIKI YSLSSQPIDH EGIKSKLSDR SPDIDNYSEE EEESFSSEQE GSDDPLHGQD
LFYEDEDLRK VKKTRRKLTS TSAITRQPNI KQKFVALLKR FKVSDEVGFG LEHVSREQIR
EVEEDLDELY DSLEMYNPSD SGPEMEETES ILSTPKPKLK PFFEGMSQSS SQTEIGSLNS
KGSLGKDTTS PMELAALEKI KSTWIKNQDD SLTETDTLEI TDQDMFGDAS TSLVVPEKVK
TPMKSSKTDL QGSASPSKVE GVHTPRQKRS TPLKERQLSK PLSERTNSSD SERSPDLGHS
TQIPRKVVYD QLNQILVSDA ALPENVILVN TTDWQGQYVA ELLQDQRKPV VCTCSTVEVQ
AVLSALLTRI QRYCNCNSSM PRPVKVAAVG GQSYLSSILR FFVKSLANKT SDWLGYMRFL
IIPLGSHPVA KYLGSVDSKY SSSFLDSGWR DLFSRSEPPV SEQLDVAGRV MQYVNGAATT
HQLPVAEAML TCRHKFPDED SYQKFIPFIG VVKVGLVEDS PSTAGDGDDS PVVSLTVPST
SPPSSSGLSR DATATPPSSP SMSSALAIVG SPNSPYGDVI GLQVDYWLGH PGERRREGDK
RDASSKNTLK SVFRSVQVSR LPHSGEAQLS GTMAMTVVTK EKNKKVPTIF LSKKPREKEV
DSKSQVIEGI SRLICSAKQQ QTMLRVSIDG VEWSDIKFFQ LAAQWPTHVK HFPVGLFSGS
KAT
//
ID PACS1_HUMAN Reviewed; 963 AA.
AC Q6VY07; Q6PJY6; Q6PKB6; Q7Z590; Q7Z5W4; Q8N8K6; Q96MW0; Q9NW92;
read moreAC Q9ULP5;
DT 13-SEP-2004, integrated into UniProtKB/Swiss-Prot.
DT 13-SEP-2004, sequence version 2.
DT 22-JAN-2014, entry version 95.
DE RecName: Full=Phosphofurin acidic cluster sorting protein 1;
DE Short=PACS-1;
GN Name=PACS1; Synonyms=KIAA1175;
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).
RA Wan L., Xiang Y., Simmen T., Thomas G.;
RT "Human PACS-1, a endosome-TGN sorting connector.";
RL Submitted (JUN-2003) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Embryo, and Fetal 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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain, Kidney, and Uterus;
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 323-963 (ISOFORM 1).
RC TISSUE=Brain;
RX PubMed=10574461; DOI=10.1093/dnares/6.5.329;
RA Hirosawa M., Nagase T., Ishikawa K., Kikuno R., Nomura N., Ohara O.;
RT "Characterization of cDNA clones selected by the GeneMark analysis
RT from size-fractionated cDNA libraries from human brain.";
RL DNA Res. 6:329-336(1999).
RN [5]
RP FUNCTION.
RX PubMed=11331585; DOI=10.1093/emboj/20.9.2191;
RA Crump C.M., Xiang Y., Thomas L., Gu F., Austin C., Tooze S.A.,
RA Thomas G.;
RT "PACS-1 binding to adaptors is required for acidic cluster motif-
RT mediated protein traffic.";
RL EMBO J. 20:2191-2201(2001).
RN [6]
RP INTERACTION WITH HIV-1 NEF.
RX PubMed=10707087; DOI=10.1038/35004038;
RA Piguet V., Wan L., Borel C., Mangasarian A., Demaurex N., Thomas G.,
RA Trono D.;
RT "HIV-1 Nef protein binds to the cellular protein PACS-1 to
RT downregulate class I major histocompatibility complexes.";
RL Nat. Cell Biol. 2:163-167(2000).
RN [7]
RP INTERACTION WITH HIV-1 NEF.
RX PubMed=12526811; DOI=10.1016/S0092-8674(02)01162-5;
RA Blagoveshchenskaya A.D., Thomas L., Feliciangeli S.F., Hung C.-H.,
RA Thomas G.;
RT "HIV-1 Nef downregulates MHC-I by a PACS-1- and PI3K-regulated ARF6
RT endocytic pathway.";
RL Cell 111:853-866(2002).
RN [8]
RP INTERACTION WITH NPHP1.
RX PubMed=16308564; DOI=10.1038/sj.emboj.7600885;
RA Schermer B., Hoepker K., Omran H., Ghenoiu C., Fliegauf M., Fekete A.,
RA Horvath J., Koettgen M., Hackl M., Zschiedrich S., Huber T.B.,
RA Kramer-Zucker A., Zentgraf H., Blaukat A., Walz G., Benzing T.;
RT "Phosphorylation by casein kinase 2 induces PACS-1 binding of
RT nephrocystin and targeting to cilia.";
RL EMBO J. 24:4415-4424(2005).
RN [9]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Embryonic kidney;
RX PubMed=17525332; DOI=10.1126/science.1140321;
RA Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III,
RA Hurov K.E., Luo J., Bakalarski C.E., Zhao Z., Solimini N.,
RA Lerenthal Y., Shiloh Y., Gygi S.P., Elledge S.J.;
RT "ATM and ATR substrate analysis reveals extensive protein networks
RT responsive to DNA damage.";
RL Science 316:1160-1166(2007).
RN [10]
RP INTERACTION WITH HIV-1 NEF.
RX PubMed=18296443; DOI=10.1074/jbc.M707572200;
RA Atkins K.M., Thomas L., Youker R.T., Harriff M.J., Pissani F., You H.,
RA Thomas G.;
RT "HIV-1 Nef binds PACS-2 to assemble a multikinase cascade that
RT triggers major histocompatibility complex class I (MHC-I) down-
RT regulation: analysis using short interfering RNA and knock-out mice.";
RL J. Biol. Chem. 283:11772-11784(2008).
RN [11]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-379; SER-430; THR-504;
RP SER-529 AND SER-534, 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 [13]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
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 [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [15]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-531, AND MASS
RP 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 [17]
RP VARIANT MRD17 TRP-203.
RX PubMed=23159249; DOI=10.1016/j.ajhg.2012.10.013;
RA Schuurs-Hoeijmakers J.H., Oh E.C., Vissers L.E., Swinkels M.E.,
RA Gilissen C., Willemsen M.A., Holvoet M., Steehouwer M., Veltman J.A.,
RA de Vries B.B., van Bokhoven H., de Brouwer A.P., Katsanis N.,
RA Devriendt K., Brunner H.G.;
RT "Recurrent de novo mutations in PACS1 cause defective cranial-neural-
RT crest migration and define a recognizable intellectual-disability
RT syndrome.";
RL Am. J. Hum. Genet. 91:1122-1127(2012).
CC -!- FUNCTION: Coat protein that is involved in the localization of
CC trans-Golgi network (TGN) membrane proteins that contain acidic
CC cluster sorting motifs. Controls the endosome-to-Golgi trafficking
CC of furin and mannose-6-phosphate receptor by connecting the
CC acidic-cluster-containing cytoplasmic domain of these molecules
CC with the adapter-protein complex-1 (AP-1) of endosomal clathrin-
CC coated membrane pits. Involved in HIV-1 nef-mediated removal of
CC MHC-I from the cell surface to the TGN.
CC -!- SUBUNIT: Interacts with HIV-1 Nef. Associates with AP-1 and AP-3
CC but not with AP-2 complexes. Interacts with NPHP1; the interaction
CC is dependent of NPHP1 phosphorylation by CK2.
CC -!- INTERACTION:
CC P67870:CSNK2B; NbExp=3; IntAct=EBI-2555014, EBI-348169;
CC Q9NZ52:GGA3; NbExp=5; IntAct=EBI-2555014, EBI-447404;
CC P11717:IGF2R; NbExp=2; IntAct=EBI-2555014, EBI-1048580;
CC -!- SUBCELLULAR LOCATION: Golgi apparatus, trans-Golgi network (By
CC similarity). Note=Localizes in the perinuclear region, probably
CC the TGN (By similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q6VY07-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q6VY07-2; Sequence=VSP_011557;
CC Note=No experimental confirmation available;
CC -!- DISEASE: Mental retardation, autosomal dominant 17 (MRD17)
CC [MIM:615009]: A disorder characterized by significantly below
CC average general intellectual functioning associated with
CC impairments in adaptive behavior and manifested during the
CC developmental period. MRD17 patients have intellectual disability
CC in combination with distinct craniofacial features and genital
CC abnormalities. Note=The disease is caused by mutations affecting
CC the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the PACS family.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH09936.1; Type=Erroneous initiation; Note=Translation N-terminally shortened;
CC Sequence=BAB71164.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC -----------------------------------------------------------------------
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DR EMBL; AY320283; AAQ67682.1; -; mRNA.
DR EMBL; AK001071; BAA91491.1; -; mRNA.
DR EMBL; AK056361; BAB71164.1; ALT_INIT; mRNA.
DR EMBL; AK096644; BAC04831.1; -; mRNA.
DR EMBL; BC003173; AAH03173.1; -; mRNA.
DR EMBL; BC010096; AAH10096.1; -; mRNA.
DR EMBL; BC009936; AAH09936.1; ALT_INIT; mRNA.
DR EMBL; BC052577; AAH52577.1; -; mRNA.
DR EMBL; BC055288; AAH55288.1; -; mRNA.
DR EMBL; AB033001; BAA86489.1; -; mRNA.
DR RefSeq; NP_060496.2; NM_018026.3.
DR UniGene; Hs.644326; -.
DR ProteinModelPortal; Q6VY07; -.
DR IntAct; Q6VY07; 8.
DR MINT; MINT-3372090; -.
DR PhosphoSite; Q6VY07; -.
DR DMDM; 52000804; -.
DR PaxDb; Q6VY07; -.
DR PRIDE; Q6VY07; -.
DR Ensembl; ENST00000320580; ENSP00000316454; ENSG00000175115.
DR GeneID; 55690; -.
DR KEGG; hsa:55690; -.
DR UCSC; uc001oha.2; human.
DR CTD; 55690; -.
DR GeneCards; GC11P065837; -.
DR HGNC; HGNC:30032; PACS1.
DR HPA; HPA038914; -.
DR MIM; 607492; gene.
DR MIM; 615009; phenotype.
DR neXtProt; NX_Q6VY07; -.
DR Orphanet; 329224; Intellectual deficit - craniofacial dysmorphism - cryptorchidism.
DR PharmGKB; PA134989529; -.
DR eggNOG; NOG279176; -.
DR HOVERGEN; HBG053488; -.
DR InParanoid; Q6VY07; -.
DR OMA; TPAPVQM; -.
DR OrthoDB; EOG7VHSX0; -.
DR PhylomeDB; Q6VY07; -.
DR Reactome; REACT_116125; Disease.
DR ChiTaRS; PACS1; human.
DR GeneWiki; PACS1; -.
DR GenomeRNAi; 55690; -.
DR NextBio; 60497; -.
DR PRO; PR:Q6VY07; -.
DR ArrayExpress; Q6VY07; -.
DR Bgee; Q6VY07; -.
DR Genevestigator; Q6VY07; -.
DR GO; GO:0030137; C:COPI-coated vesicle; IEA:Ensembl.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR GO; GO:0000042; P:protein targeting to Golgi; IEA:Ensembl.
DR GO; GO:0072661; P:protein targeting to plasma membrane; IMP:BHF-UCL.
DR GO; GO:0050690; P:regulation of defense response to virus by virus; TAS:Reactome.
DR GO; GO:0016032; P:viral process; TAS:Reactome.
DR InterPro; IPR019381; Phosphofurin_acidic_CS-1.
DR Pfam; PF10254; Pacs-1; 1.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; Coiled coil; Complete proteome;
KW Disease mutation; Golgi apparatus; Host-virus interaction;
KW Mental retardation; Phosphoprotein; Polymorphism; Reference proteome.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 963 Phosphofurin acidic cluster sorting
FT protein 1.
FT /FTId=PRO_0000058171.
FT REGION 168 175 Involved in binding to AP-1.
FT COILED 353 377 Potential.
FT COMPBIAS 5 44 Gly-rich.
FT COMPBIAS 35 40 Poly-Gln.
FT COMPBIAS 55 84 Ser-rich.
FT COMPBIAS 62 65 Poly-Ala.
FT COMPBIAS 112 115 Poly-Ser.
FT COMPBIAS 279 283 Poly-Glu.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 379 379 Phosphoserine.
FT MOD_RES 430 430 Phosphoserine.
FT MOD_RES 504 504 Phosphothreonine.
FT MOD_RES 529 529 Phosphoserine.
FT MOD_RES 531 531 Phosphoserine.
FT MOD_RES 534 534 Phosphoserine.
FT VAR_SEQ 917 963 AKQQQTMLRVSIDGVEWSDIKFFQLAAQWPTHVKHFPVGLF
FT SGSKAT -> SPSLGPSLGPDPSSQPGFPPAGSFPPCHLPL
FT TNPGSEPLIPDRPCSQEWLRTQGPSPALCTPQPGHLRPTAP
FT LELFSCPLTPSQKFLHRTSF (in isoform 2).
FT /FTId=VSP_011557.
FT VARIANT 203 203 R -> W (in MRD17).
FT /FTId=VAR_069534.
FT VARIANT 302 302 F -> L (in dbSNP:rs12798852).
FT /FTId=VAR_053797.
FT CONFLICT 171 220 Missing (in Ref. 2; BAC04831).
FT CONFLICT 649 649 K -> M (in Ref. 2; BAA91491).
FT CONFLICT 771 771 P -> S (in Ref. 2; BAC04831).
FT CONFLICT 803 803 S -> N (in Ref. 1; AAQ67682).
FT CONFLICT 882 882 K -> L (in Ref. 1; AAQ67682).
SQ SEQUENCE 963 AA; 104898 MW; 0F6B2CA24F7CD567 CRC64;
MAERGGAGGG PGGAGGGSGQ RGSGVAQSPQ QPPPQQQQQQ PPQQPTPPKL AQATSSSSST
SAAAASSSSS STSTSMAVAV ASGSAPPGGP GPGRTPAPVQ MNLYATWEVD RSSSSCVPRL
FSLTLKKLVM LKEMDKDLNS VVIAVKLQGS KRILRSNEIV LPASGLVETE LQLTFSLQYP
HFLKRDANKL QIMLQRRKRY KNRTILGYKT LAVGLINMAE VMQHPNEGAL VLGLHSNVKD
VSVPVAEIKI YSLSSQPIDH EGIKSKLSDR SPDIDNYSEE EEESFSSEQE GSDDPLHGQD
LFYEDEDLRK VKKTRRKLTS TSAITRQPNI KQKFVALLKR FKVSDEVGFG LEHVSREQIR
EVEEDLDELY DSLEMYNPSD SGPEMEETES ILSTPKPKLK PFFEGMSQSS SQTEIGSLNS
KGSLGKDTTS PMELAALEKI KSTWIKNQDD SLTETDTLEI TDQDMFGDAS TSLVVPEKVK
TPMKSSKTDL QGSASPSKVE GVHTPRQKRS TPLKERQLSK PLSERTNSSD SERSPDLGHS
TQIPRKVVYD QLNQILVSDA ALPENVILVN TTDWQGQYVA ELLQDQRKPV VCTCSTVEVQ
AVLSALLTRI QRYCNCNSSM PRPVKVAAVG GQSYLSSILR FFVKSLANKT SDWLGYMRFL
IIPLGSHPVA KYLGSVDSKY SSSFLDSGWR DLFSRSEPPV SEQLDVAGRV MQYVNGAATT
HQLPVAEAML TCRHKFPDED SYQKFIPFIG VVKVGLVEDS PSTAGDGDDS PVVSLTVPST
SPPSSSGLSR DATATPPSSP SMSSALAIVG SPNSPYGDVI GLQVDYWLGH PGERRREGDK
RDASSKNTLK SVFRSVQVSR LPHSGEAQLS GTMAMTVVTK EKNKKVPTIF LSKKPREKEV
DSKSQVIEGI SRLICSAKQQ QTMLRVSIDG VEWSDIKFFQ LAAQWPTHVK HFPVGLFSGS
KAT
//
MIM
607492
*RECORD*
*FIELD* NO
607492
*FIELD* TI
*607492 PHOSPHOFURIN ACIDIC CLUSTER SORTING PROTEIN 1; PACS1
*FIELD* TX
DESCRIPTION
read more
PACS1 is a trans-Golgi-membrane traffic regulator that directs protein
cargo and several viral envelope proteins. It is upregulated during
human embryonic brain development and has low expression after birth
(summary by Schuurs-Hoeijmakers et al., 2012).
CLONING
By yeast 2-hybrid screening of a mouse embryo cDNA library to identify
cytosolic proteins that bind directly to the phosphorylated furin
(136950) cytosolic domain, Wan et al. (1998) identified cDNAs encoding
Pacs1. Screening of a rat brain cDNA library with the Pacs1 sequences
yielded 2 cDNAs representing splice variants. The larger variant,
Pacs1a, has 961 amino acids, and the smaller variant, Pacs1b, has 559
amino acids. Both proteins contain the 140-amino acid furin-binding
region (val115 to pro255). Northern blot analysis using
transcript-specific probes showed that both Pacs1 variants were
expressed ubiquitously, with the 4.4-kb Pacs1a transcript expressed more
than 20-fold higher than the 3.6-kb Pacs1b transcript. Wan et al. (1998)
also identified human ESTs containing PACS1 sequences.
GENE FUNCTION
Wan et al. (1998) reported that Pacs1 directs the trans-Golgi network
(TGN) localization of furin by binding to its phosphorylated cytosolic
domain. Antisense studies showed that TGN localization of furin and
mannose 6-phosphate receptor (M6PR; 154540), but not TGN46 (603062), is
strictly dependent on Pacs1. Analyses in vitro and in vivo showed that
Pacs1 has properties of a coat protein and connects furin to components
of the clathrin-sorting machinery. Cell-free assays indicated TGN
localization of furin is directed by a Pacs1-mediated retrieval step.
Together, these findings explained a mechanism by which membrane
proteins in mammalian cells are localized to the TGN.
Blagoveshchenskaya et al. (2002) showed that the human immunodeficiency
virus (HIV)-1 multifunctional early gene product Nef and cellular PACS1
combine to usurp the ARF6 (600464) endocytic pathway by a
phosphatidylinositol 3-kinase (PI3K; see 171833)-dependent process and
downregulate cell surface major histocompatibility complex (MHC) class I
molecules to the TGN. They found that this mechanism requires the
hierarchical actions of 3 Nef motifs, the acidic cluster
glu62-glu63-glu64-glu65, the SH3 domain-binding site pro72-X-X-pro75,
and met20, in controlling PACS1-dependent sorting to the TGN, ARF6
activation, and sequestering internalized MHC class I molecules to the
TGN, respectively.
Polycystin-2 (PKD2; 173910) functions as a calcium-permeable
nonselective cation channel at the plasma membrane or ER. Kottgen et al.
(2005) found that the subcellular localization and function of
polycystin-2 were directed by PACS1 and PACS2 (610423), which recognized
an acidic cluster in the C-terminal domain of polycystin-2. Binding to
these adaptor proteins was regulated by the phosphorylation of
polycystin-2 on ser812 by casein kinase-2 (see CSNK2A1; 115440),
required for the routing of polycystin-2 between ER, Golgi, and the
plasma membrane compartments. Kottgen et al. (2005) concluded that PACS1
and PACS2 are involved in ion channel trafficking, directing acid
cluster-containing ion channels to distinct subcellular compartments.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the PACS1
gene to chromosome 11 (TMAP RH18211). By radiation hybrid and genomic
database analysis, Simmen et al. (2005) mapped the PACS1 gene to
chromosome 11q13.1.
MOLECULAR GENETICS
Schuurs-Hoeijmakers et al. (2012) identified a recurrent de novo
missense mutation in PACS1, an arginine-to-tryptophan substitution at
position 203 (R203W; 607492.0001), in the furin (cargo) binding region
directly adjacent to the CK2 binding motif. Schuurs-Hoeijmakers et al.
(2012) found that altered PACS1 forms cytoplasmic aggregates in vitro
with concomitant increased stability and showed impaired binding to an
isoform-specific variant of TRPV4 (605427), but not the full-length
protein. Furthermore, consistent with the human pathology, expression of
mutant PACS1 mRNA in zebrafish embryos induced craniofacial defects most
likely in a dominant-negative fashion. The phenotype was driven by
aberrant specification and migration of SOX10 (602229)-positive cranial,
but not enteric, neural crest cells.
*FIELD* AV
.0001
MENTAL RETARDATION, AUTOSOMAL DOMINANT 17
PACS1, ARG203TRP
In 2 boys with mental retardation and a strikingly similar facial
appearance (MRD17; 615009), Schuurs-Hoeijmakers et al. (2012) identified
the same de novo mutation in the PACS1 gene: a 607C-T transition
resulting in an arg-to-trp substitution at residue 203 (R203W). This
mutation was not identified in 150 alleles from the Dutch population, in
2,304 from the local variant database, or in 7,020 alleles of European
American origin from the NHLBI Exome Sequencing Project.
*FIELD* RF
1. Blagoveshchenskaya, A. D.; Thomas, L.; Feliciangeli, S. F.; Hung,
C.-H.; Thomas, G.: HIV-1 Nef downregulates MHC-I by a PACS-1- and
PI3K-regulated ARF6 endocytic pathway. Cell 111: 853-866, 2002.
2. Kottgen, M.; Benzing, T.; Simmen, T.; Tauber, R.; Buchholz, B.;
Feliciangeli, S.; Huber, T. B.; Schermer, B.; Kramer-Zucker, A.; Hopker,
K.; Simmen, K. C.; Tschucke, C. C.; Sandford, R.; Kim, E.; Thomas,
G.; Walz, G.: Trafficking of TRPP2 by PACS proteins represents a
novel mechanism of ion channel regulation. EMBO J. 24: 705-716,
2005.
3. Schuurs-Hoeijmakers, J. H. M.; Oh, E. C.; Vissers, L. E. L. M.;
Swinkels, M. E. M.; Gilissen, C.; Willemsen, M. A.; Holvoet, M.; Steehouwer,
M.; Veltman, J. A.; de Vries, B. B. A.; van Bokhoven, H.; de Brouwer,
A. P. M.; Katsanis, N.; Devriendt, K.; Brunner, H. G.: Recurrent
de novo mutations in PACS1 cause defective cranial neural-crest migration
and define a recognizable intellectual-disability syndrome. Am. J.
Hum. Genet. 91: 1122-1127, 2012.
4. Simmen, T.; Aslan, J. E.; Blagoveshchenskaya, A. D.; Thomas, L.;
Wan, L.; Xiang, Y.; Feliciangeli, S. F.; Hung, C.-H.; Crump, C. M.;
Thomas, G.: PACS-2 controls endoplasmic reticulum-mitochondria communication
and Bid-mediated apoptosis. EMBO J. 24: 717-729, 2005. Note: Erratum:
EMBO J. 24: 1301 only, 2005.
5. Wan, L.; Molloy, S. S.; Thomas, L.; Liu, G.; Xiang, Y.; Rybak,
S. L.; Thomas, G.: PACS-1 defines a novel gene family of cytosolic
sorting proteins required for trans-Golgi network localization. Cell 94:
205-216, 1998.
*FIELD* CN
Ada Hamosh - updated: 1/8/2013
Patricia A. Hartz - updated: 9/22/2006
*FIELD* CD
Stylianos E. Antonarakis: 1/17/2003
*FIELD* ED
terry: 03/14/2013
alopez: 1/9/2013
terry: 1/8/2013
wwang: 9/22/2006
mgross: 1/17/2003
*RECORD*
*FIELD* NO
607492
*FIELD* TI
*607492 PHOSPHOFURIN ACIDIC CLUSTER SORTING PROTEIN 1; PACS1
*FIELD* TX
DESCRIPTION
read more
PACS1 is a trans-Golgi-membrane traffic regulator that directs protein
cargo and several viral envelope proteins. It is upregulated during
human embryonic brain development and has low expression after birth
(summary by Schuurs-Hoeijmakers et al., 2012).
CLONING
By yeast 2-hybrid screening of a mouse embryo cDNA library to identify
cytosolic proteins that bind directly to the phosphorylated furin
(136950) cytosolic domain, Wan et al. (1998) identified cDNAs encoding
Pacs1. Screening of a rat brain cDNA library with the Pacs1 sequences
yielded 2 cDNAs representing splice variants. The larger variant,
Pacs1a, has 961 amino acids, and the smaller variant, Pacs1b, has 559
amino acids. Both proteins contain the 140-amino acid furin-binding
region (val115 to pro255). Northern blot analysis using
transcript-specific probes showed that both Pacs1 variants were
expressed ubiquitously, with the 4.4-kb Pacs1a transcript expressed more
than 20-fold higher than the 3.6-kb Pacs1b transcript. Wan et al. (1998)
also identified human ESTs containing PACS1 sequences.
GENE FUNCTION
Wan et al. (1998) reported that Pacs1 directs the trans-Golgi network
(TGN) localization of furin by binding to its phosphorylated cytosolic
domain. Antisense studies showed that TGN localization of furin and
mannose 6-phosphate receptor (M6PR; 154540), but not TGN46 (603062), is
strictly dependent on Pacs1. Analyses in vitro and in vivo showed that
Pacs1 has properties of a coat protein and connects furin to components
of the clathrin-sorting machinery. Cell-free assays indicated TGN
localization of furin is directed by a Pacs1-mediated retrieval step.
Together, these findings explained a mechanism by which membrane
proteins in mammalian cells are localized to the TGN.
Blagoveshchenskaya et al. (2002) showed that the human immunodeficiency
virus (HIV)-1 multifunctional early gene product Nef and cellular PACS1
combine to usurp the ARF6 (600464) endocytic pathway by a
phosphatidylinositol 3-kinase (PI3K; see 171833)-dependent process and
downregulate cell surface major histocompatibility complex (MHC) class I
molecules to the TGN. They found that this mechanism requires the
hierarchical actions of 3 Nef motifs, the acidic cluster
glu62-glu63-glu64-glu65, the SH3 domain-binding site pro72-X-X-pro75,
and met20, in controlling PACS1-dependent sorting to the TGN, ARF6
activation, and sequestering internalized MHC class I molecules to the
TGN, respectively.
Polycystin-2 (PKD2; 173910) functions as a calcium-permeable
nonselective cation channel at the plasma membrane or ER. Kottgen et al.
(2005) found that the subcellular localization and function of
polycystin-2 were directed by PACS1 and PACS2 (610423), which recognized
an acidic cluster in the C-terminal domain of polycystin-2. Binding to
these adaptor proteins was regulated by the phosphorylation of
polycystin-2 on ser812 by casein kinase-2 (see CSNK2A1; 115440),
required for the routing of polycystin-2 between ER, Golgi, and the
plasma membrane compartments. Kottgen et al. (2005) concluded that PACS1
and PACS2 are involved in ion channel trafficking, directing acid
cluster-containing ion channels to distinct subcellular compartments.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the PACS1
gene to chromosome 11 (TMAP RH18211). By radiation hybrid and genomic
database analysis, Simmen et al. (2005) mapped the PACS1 gene to
chromosome 11q13.1.
MOLECULAR GENETICS
Schuurs-Hoeijmakers et al. (2012) identified a recurrent de novo
missense mutation in PACS1, an arginine-to-tryptophan substitution at
position 203 (R203W; 607492.0001), in the furin (cargo) binding region
directly adjacent to the CK2 binding motif. Schuurs-Hoeijmakers et al.
(2012) found that altered PACS1 forms cytoplasmic aggregates in vitro
with concomitant increased stability and showed impaired binding to an
isoform-specific variant of TRPV4 (605427), but not the full-length
protein. Furthermore, consistent with the human pathology, expression of
mutant PACS1 mRNA in zebrafish embryos induced craniofacial defects most
likely in a dominant-negative fashion. The phenotype was driven by
aberrant specification and migration of SOX10 (602229)-positive cranial,
but not enteric, neural crest cells.
*FIELD* AV
.0001
MENTAL RETARDATION, AUTOSOMAL DOMINANT 17
PACS1, ARG203TRP
In 2 boys with mental retardation and a strikingly similar facial
appearance (MRD17; 615009), Schuurs-Hoeijmakers et al. (2012) identified
the same de novo mutation in the PACS1 gene: a 607C-T transition
resulting in an arg-to-trp substitution at residue 203 (R203W). This
mutation was not identified in 150 alleles from the Dutch population, in
2,304 from the local variant database, or in 7,020 alleles of European
American origin from the NHLBI Exome Sequencing Project.
*FIELD* RF
1. Blagoveshchenskaya, A. D.; Thomas, L.; Feliciangeli, S. F.; Hung,
C.-H.; Thomas, G.: HIV-1 Nef downregulates MHC-I by a PACS-1- and
PI3K-regulated ARF6 endocytic pathway. Cell 111: 853-866, 2002.
2. Kottgen, M.; Benzing, T.; Simmen, T.; Tauber, R.; Buchholz, B.;
Feliciangeli, S.; Huber, T. B.; Schermer, B.; Kramer-Zucker, A.; Hopker,
K.; Simmen, K. C.; Tschucke, C. C.; Sandford, R.; Kim, E.; Thomas,
G.; Walz, G.: Trafficking of TRPP2 by PACS proteins represents a
novel mechanism of ion channel regulation. EMBO J. 24: 705-716,
2005.
3. Schuurs-Hoeijmakers, J. H. M.; Oh, E. C.; Vissers, L. E. L. M.;
Swinkels, M. E. M.; Gilissen, C.; Willemsen, M. A.; Holvoet, M.; Steehouwer,
M.; Veltman, J. A.; de Vries, B. B. A.; van Bokhoven, H.; de Brouwer,
A. P. M.; Katsanis, N.; Devriendt, K.; Brunner, H. G.: Recurrent
de novo mutations in PACS1 cause defective cranial neural-crest migration
and define a recognizable intellectual-disability syndrome. Am. J.
Hum. Genet. 91: 1122-1127, 2012.
4. Simmen, T.; Aslan, J. E.; Blagoveshchenskaya, A. D.; Thomas, L.;
Wan, L.; Xiang, Y.; Feliciangeli, S. F.; Hung, C.-H.; Crump, C. M.;
Thomas, G.: PACS-2 controls endoplasmic reticulum-mitochondria communication
and Bid-mediated apoptosis. EMBO J. 24: 717-729, 2005. Note: Erratum:
EMBO J. 24: 1301 only, 2005.
5. Wan, L.; Molloy, S. S.; Thomas, L.; Liu, G.; Xiang, Y.; Rybak,
S. L.; Thomas, G.: PACS-1 defines a novel gene family of cytosolic
sorting proteins required for trans-Golgi network localization. Cell 94:
205-216, 1998.
*FIELD* CN
Ada Hamosh - updated: 1/8/2013
Patricia A. Hartz - updated: 9/22/2006
*FIELD* CD
Stylianos E. Antonarakis: 1/17/2003
*FIELD* ED
terry: 03/14/2013
alopez: 1/9/2013
terry: 1/8/2013
wwang: 9/22/2006
mgross: 1/17/2003
MIM
615009
*RECORD*
*FIELD* NO
615009
*FIELD* TI
#615009 MENTAL RETARDATION, AUTOSOMAL DOMINANT 17; MRD17
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
read moreautosomal dominant mental retardation-17 (MRD17) is caused by
heterozygous mutation in the PACS1 gene (607492) on chromosome 11q13.
DESCRIPTION
MRD17 was reported in 2 unrelated males with the same de novo mutation
in PACS1 causing mental retardation, distinct craniofacial features, and
genital abnormalities (Schuurs-Hoeijmakers et al., 2012).
CLINICAL FEATURES
Schuurs-Hoeijmakers et al. (2012) reported 2 boys from a cohort of 5,000
individuals with intellectual disability who had remarkable similarity
in facial features. Both had a low anterior hairline, hypertelorism with
downslanting palpebral fissures, mild synophrys with highly arched
eyebrows, long eyelashes, bulbous nose, flat philtrum, large low-set
ears, wide mouth with downturned corners, thin upper lip, and diastema
of the teeth. One boy had an IQ of less than 50; the other boy had an IQ
of 53. The first boy had a single umbilical artery, unilateral
cryptorchidism, malrotation, as well as widely spaced nipples, slender
fingers with broad thumbs, clubbed nails, a single transverse palmar
cleft on the left hand, and pes planus. MRI showed a cavum septum
pellucidum but was otherwise normal. The second boy was large at birth
and had strikingly similar dysmorphic facial features. He also had
cryptorchidism. On neurologic examination he had some balance problems
and mild dysarthric speech. He was hypotonic. MRI showed partial
agenesis of the cerebellum vermis and hypoplasia of the cerebellar
hemispheres, more pronounced on the right side.
MOLECULAR GENETICS
In 2 boys with mental retardation and similar dysmorphic facial
features, Schuurs-Hoeijmakers et al. (2012) identified identical de novo
heterozygous mutations in the PACS1 gene: a C-to-T transition at
nucleotide 607, resulting in an arg-to-trp substitution at codon 203
(R203W; 607492.0001). This mutation was not identified in 150 alleles
from the Dutch population, in 2,304 from the local variant database, or
in 7,020 alleles of European American origin from the NHLBI Exome
Sequencing Project.
*FIELD* RF
1. Schuurs-Hoeijmakers, J. H. M.; Oh, E. C.; Vissers, L. E. L. M.;
Swinkels, M. E. M.; Gilissen, C.; Willemsen, M. A.; Holvoet, M.; Steehouwer,
M.; Veltman, J. A.; de Vries, B. B. A.; van Bokhoven, H.; de Brouwer,
A. P. M.; Katsanis, N.; Devriendt, K.; Brunner, H. G.: Recurrent
de novo mutations in PACS1 cause defective cranial neural-crest migration
and define a recognizable intellectual-disability syndrome. Am. J.
Hum. Genet. 91: 1122-1127, 2012.
*FIELD* CD
Ada Hamosh: 1/9/2013
*FIELD* ED
alopez: 01/09/2013
alopez: 1/9/2013
*RECORD*
*FIELD* NO
615009
*FIELD* TI
#615009 MENTAL RETARDATION, AUTOSOMAL DOMINANT 17; MRD17
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
read moreautosomal dominant mental retardation-17 (MRD17) is caused by
heterozygous mutation in the PACS1 gene (607492) on chromosome 11q13.
DESCRIPTION
MRD17 was reported in 2 unrelated males with the same de novo mutation
in PACS1 causing mental retardation, distinct craniofacial features, and
genital abnormalities (Schuurs-Hoeijmakers et al., 2012).
CLINICAL FEATURES
Schuurs-Hoeijmakers et al. (2012) reported 2 boys from a cohort of 5,000
individuals with intellectual disability who had remarkable similarity
in facial features. Both had a low anterior hairline, hypertelorism with
downslanting palpebral fissures, mild synophrys with highly arched
eyebrows, long eyelashes, bulbous nose, flat philtrum, large low-set
ears, wide mouth with downturned corners, thin upper lip, and diastema
of the teeth. One boy had an IQ of less than 50; the other boy had an IQ
of 53. The first boy had a single umbilical artery, unilateral
cryptorchidism, malrotation, as well as widely spaced nipples, slender
fingers with broad thumbs, clubbed nails, a single transverse palmar
cleft on the left hand, and pes planus. MRI showed a cavum septum
pellucidum but was otherwise normal. The second boy was large at birth
and had strikingly similar dysmorphic facial features. He also had
cryptorchidism. On neurologic examination he had some balance problems
and mild dysarthric speech. He was hypotonic. MRI showed partial
agenesis of the cerebellum vermis and hypoplasia of the cerebellar
hemispheres, more pronounced on the right side.
MOLECULAR GENETICS
In 2 boys with mental retardation and similar dysmorphic facial
features, Schuurs-Hoeijmakers et al. (2012) identified identical de novo
heterozygous mutations in the PACS1 gene: a C-to-T transition at
nucleotide 607, resulting in an arg-to-trp substitution at codon 203
(R203W; 607492.0001). This mutation was not identified in 150 alleles
from the Dutch population, in 2,304 from the local variant database, or
in 7,020 alleles of European American origin from the NHLBI Exome
Sequencing Project.
*FIELD* RF
1. Schuurs-Hoeijmakers, J. H. M.; Oh, E. C.; Vissers, L. E. L. M.;
Swinkels, M. E. M.; Gilissen, C.; Willemsen, M. A.; Holvoet, M.; Steehouwer,
M.; Veltman, J. A.; de Vries, B. B. A.; van Bokhoven, H.; de Brouwer,
A. P. M.; Katsanis, N.; Devriendt, K.; Brunner, H. G.: Recurrent
de novo mutations in PACS1 cause defective cranial neural-crest migration
and define a recognizable intellectual-disability syndrome. Am. J.
Hum. Genet. 91: 1122-1127, 2012.
*FIELD* CD
Ada Hamosh: 1/9/2013
*FIELD* ED
alopez: 01/09/2013
alopez: 1/9/2013