PKHA3_HUMAN
ID PKHA3_HUMAN Reviewed; 300 AA.
AC Q9HB20; Q4ZG69; Q86TQ1; Q9NXT3;
DT 29-MAR-2004, integrated into UniProtKB/Swiss-Prot.
DT 29-MAR-2004, sequence version 2.
DT 03-AUG-2022, entry version 157.
DE RecName: Full=Pleckstrin homology domain-containing family A member 3;
DE Short=PH domain-containing family A member 3;
DE AltName: Full=Phosphatidylinositol-four-phosphate adapter protein 1 {ECO:0000303|PubMed:30659099};
DE Short=FAPP-1;
DE Short=Phosphoinositol 4-phosphate adapter protein 1;
GN Name=PLEKHA3; Synonyms=FAPP1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND FUNCTION.
RX PubMed=11001876; DOI=10.1042/0264-6021:3510019;
RA Dowler S.J., Currie R.A., Campbell D.G., Deak M., Kular G., Downes C.P.,
RA Alessi D.R.;
RT "Identification of pleckstrin-homology-domain-containing proteins with
RT novel phosphoinositide-binding specificities.";
RL Biochem. J. 351:19-31(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain, and Colon;
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., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., 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., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA 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 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., Minx P.,
RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA Strong C.M., 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., Swearengen-Shahid S.,
RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA Cox D.R., Huang X., 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., Waterston R.H.,
RA Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT 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., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
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 project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH ARF1, AND DOMAIN PH.
RX PubMed=15107860; DOI=10.1038/ncb1119;
RA Godi A., Di Campli A., Konstantakopoulos A., Di Tullio G., Alessi D.R.,
RA Kular G.S., Daniele T., Marra P., Lucocq J.M., De Matteis M.A.;
RT "FAPPs control Golgi-to-cell-surface membrane traffic by binding to ARF and
RT PtdIns(4)P.";
RL Nat. Cell Biol. 6:393-404(2004).
RN [7]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-236 AND SER-244, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [9]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH SACM1L AND VAPA AND/OR
RP VAPB.
RX PubMed=30659099; DOI=10.1083/jcb.201812021;
RA Venditti R., Masone M.C., Rega L.R., Di Tullio G., Santoro M.,
RA Polishchuk E., Serrano I.C., Olkkonen V.M., Harada A., Medina D.L.,
RA La Montagna R., De Matteis M.A.;
RT "The activity of Sac1 across ER-TGN contact sites requires the four-
RT phosphate-adaptor-protein-1.";
RL J. Cell Biol. 218:783-797(2019).
RN [10]
RP STRUCTURE BY NMR OF 1-100.
RX PubMed=20300118; DOI=10.1038/embor.2010.28;
RA Lenoir M., Coskun U., Grzybek M., Cao X., Buschhorn S.B., James J.,
RA Simons K., Overduin M.;
RT "Structural basis of wedging the Golgi membrane by FAPP pleckstrin homology
RT domains.";
RL EMBO Rep. 11:279-284(2010).
RN [11]
RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 1-99 OF MUTANT SER-94, AND
RP INTERACTION WITH ARF1.
RX PubMed=21454700; DOI=10.1074/jbc.m111.233015;
RA He J., Scott J.L., Heroux A., Roy S., Lenoir M., Overduin M.,
RA Stahelin R.V., Kutateladze T.G.;
RT "Molecular basis of phosphatidylinositol 4-phosphate and ARF1 GTPase
RT recognition by the FAPP1 pleckstrin homology (PH) domain.";
RL J. Biol. Chem. 286:18650-18657(2011).
CC -!- FUNCTION: Plays a role in regulation of vesicular cargo transport from
CC the trans-Golgi network (TGN) to the plasma membrane (PubMed:15107860).
CC Regulates Golgi phosphatidylinositol 4-phosphate (PtdIns(4)P) levels
CC and activates the PtdIns(4)P phosphatase activity of SACM1L when it
CC binds PtdIns(4)P in 'trans' configuration (PubMed:30659099). Binds
CC preferentially to PtdIns(4)P (PubMed:11001876, PubMed:15107860).
CC Negatively regulates APOB secretion from hepatocytes (PubMed:30659099).
CC {ECO:0000269|PubMed:11001876, ECO:0000269|PubMed:15107860,
CC ECO:0000269|PubMed:30659099}.
CC -!- SUBUNIT: Interacts with GTP-bound ARF1 (PubMed:15107860,
CC PubMed:21454700). Interacts with SACM1L and VAPA and/or VAPB to form a
CC ternary complex (PubMed:30659099). {ECO:0000269|PubMed:15107860,
CC ECO:0000269|PubMed:21454700, ECO:0000269|PubMed:30659099}.
CC -!- INTERACTION:
CC Q9HB20; Q7L591-3: DOK3; NbExp=3; IntAct=EBI-11079894, EBI-10694655;
CC Q9HB20; A0A024R8L2: hCG_1987119; NbExp=3; IntAct=EBI-11079894, EBI-14103818;
CC Q9HB20; Q9UBU8-2: MORF4L1; NbExp=3; IntAct=EBI-11079894, EBI-10288852;
CC Q9HB20; Q9BRJ2: MRPL45; NbExp=3; IntAct=EBI-11079894, EBI-2514313;
CC Q9HB20; Q9HB20: PLEKHA3; NbExp=6; IntAct=EBI-11079894, EBI-11079894;
CC Q9HB20; O43148: RNMT; NbExp=3; IntAct=EBI-11079894, EBI-877832;
CC Q9HB20; O14492-2: SH2B2; NbExp=3; IntAct=EBI-11079894, EBI-19952306;
CC Q9HB20; O95988: TCL1B; NbExp=3; IntAct=EBI-11079894, EBI-727338;
CC -!- SUBCELLULAR LOCATION: Golgi apparatus, trans-Golgi network membrane
CC {ECO:0000269|PubMed:15107860}; Peripheral membrane protein
CC {ECO:0000269|PubMed:15107860}. Note=Localizes to ER-trans Golgi network
CC (TGN) contacts sites. {ECO:0000269|PubMed:30659099}.
CC -!- TISSUE SPECIFICITY: Widely expressed.
CC -!- DOMAIN: The PH domain binds the small GTPase ARF1 and
CC phosphatidylinositol-4-phosphate (PtdIns4P) with high selectivity, and
CC is required for its recruitment to the trans-Golgi network (TGN).
CC {ECO:0000269|PubMed:15107860}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA90927.1; Type=Erroneous initiation; Evidence={ECO:0000305};
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DR EMBL; AF286162; AAG15199.1; -; mRNA.
DR EMBL; AK000074; BAA90927.1; ALT_INIT; mRNA.
DR EMBL; AK314459; BAG37067.1; -; mRNA.
DR EMBL; AC009948; AAX88884.1; -; Genomic_DNA.
DR EMBL; CH471058; EAX11026.1; -; Genomic_DNA.
DR EMBL; BC044567; AAH44567.1; -; mRNA.
DR CCDS; CCDS33336.1; -.
DR RefSeq; NP_061964.3; NM_019091.3.
DR PDB; 2KCJ; NMR; -; A=1-100.
DR PDB; 2MDX; NMR; -; A=1-100.
DR PDB; 3RCP; X-ray; 1.90 A; A=1-99.
DR PDBsum; 2KCJ; -.
DR PDBsum; 2MDX; -.
DR PDBsum; 3RCP; -.
DR AlphaFoldDB; Q9HB20; -.
DR BMRB; Q9HB20; -.
DR SMR; Q9HB20; -.
DR BioGRID; 122427; 35.
DR IntAct; Q9HB20; 12.
DR STRING; 9606.ENSP00000234453; -.
DR GlyGen; Q9HB20; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q9HB20; -.
DR PhosphoSitePlus; Q9HB20; -.
DR BioMuta; PLEKHA3; -.
DR DMDM; 48474646; -.
DR EPD; Q9HB20; -.
DR jPOST; Q9HB20; -.
DR MassIVE; Q9HB20; -.
DR MaxQB; Q9HB20; -.
DR PaxDb; Q9HB20; -.
DR PeptideAtlas; Q9HB20; -.
DR PRIDE; Q9HB20; -.
DR ProteomicsDB; 81473; -.
DR Antibodypedia; 33940; 121 antibodies from 19 providers.
DR DNASU; 65977; -.
DR Ensembl; ENST00000234453.10; ENSP00000234453.4; ENSG00000116095.11.
DR GeneID; 65977; -.
DR KEGG; hsa:65977; -.
DR MANE-Select; ENST00000234453.10; ENSP00000234453.4; NM_019091.4; NP_061964.3.
DR UCSC; uc002umn.4; human.
DR CTD; 65977; -.
DR DisGeNET; 65977; -.
DR GeneCards; PLEKHA3; -.
DR HGNC; HGNC:14338; PLEKHA3.
DR HPA; ENSG00000116095; Low tissue specificity.
DR MIM; 607774; gene.
DR neXtProt; NX_Q9HB20; -.
DR OpenTargets; ENSG00000116095; -.
DR PharmGKB; PA33403; -.
DR VEuPathDB; HostDB:ENSG00000116095; -.
DR eggNOG; ENOG502QPTX; Eukaryota.
DR GeneTree; ENSGT00940000155850; -.
DR HOGENOM; CLU_062751_0_0_1; -.
DR InParanoid; Q9HB20; -.
DR OMA; VHHDETH; -.
DR OrthoDB; 952122at2759; -.
DR PhylomeDB; Q9HB20; -.
DR TreeFam; TF317467; -.
DR PathwayCommons; Q9HB20; -.
DR Reactome; R-HSA-1660499; Synthesis of PIPs at the plasma membrane.
DR SignaLink; Q9HB20; -.
DR BioGRID-ORCS; 65977; 16 hits in 1082 CRISPR screens.
DR ChiTaRS; PLEKHA3; human.
DR EvolutionaryTrace; Q9HB20; -.
DR GenomeRNAi; 65977; -.
DR Pharos; Q9HB20; Tbio.
DR PRO; PR:Q9HB20; -.
DR Proteomes; UP000005640; Chromosome 2.
DR RNAct; Q9HB20; protein.
DR Bgee; ENSG00000116095; Expressed in epithelial cell of pancreas and 187 other tissues.
DR ExpressionAtlas; Q9HB20; baseline and differential.
DR Genevisible; Q9HB20; HS.
DR GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR GO; GO:0005794; C:Golgi apparatus; IDA:HPA.
DR GO; GO:0000139; C:Golgi membrane; TAS:Reactome.
DR GO; GO:1902387; F:ceramide 1-phosphate binding; IBA:GO_Central.
DR GO; GO:1902388; F:ceramide 1-phosphate transfer activity; IBA:GO_Central.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0070273; F:phosphatidylinositol-4-phosphate binding; IDA:UniProtKB.
DR GO; GO:0035627; P:ceramide transport; IBA:GO_Central.
DR GO; GO:0120009; P:intermembrane lipid transfer; IBA:GO_Central.
DR Gene3D; 2.30.29.30; -; 1.
DR InterPro; IPR000648; Oxysterol-bd.
DR InterPro; IPR011993; PH-like_dom_sf.
DR InterPro; IPR001849; PH_domain.
DR PANTHER; PTHR10972; PTHR10972; 1.
DR Pfam; PF00169; PH; 1.
DR SMART; SM00233; PH; 1.
DR PROSITE; PS50003; PH_DOMAIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Golgi apparatus; Lipid-binding; Membrane; Phosphoprotein;
KW Reference proteome.
FT CHAIN 1..300
FT /note="Pleckstrin homology domain-containing family A
FT member 3"
FT /id="PRO_0000053878"
FT DOMAIN 1..93
FT /note="PH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00145"
FT REGION 1..100
FT /note="Interaction with SACM1L"
FT /evidence="ECO:0000269|PubMed:30659099"
FT REGION 97..300
FT /note="Interaction with VAPA and VAPB"
FT /evidence="ECO:0000269|PubMed:30659099"
FT REGION 197..300
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 202..231
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 232..262
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 236
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 244
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT CONFLICT 284
FT /note="M -> T (in Ref. 1; AAG15199)"
FT /evidence="ECO:0000305"
FT STRAND 2..8
FT /evidence="ECO:0007829|PDB:3RCP"
FT TURN 11..13
FT /evidence="ECO:0007829|PDB:3RCP"
FT STRAND 15..23
FT /evidence="ECO:0007829|PDB:3RCP"
FT STRAND 26..32
FT /evidence="ECO:0007829|PDB:3RCP"
FT HELIX 33..38
FT /evidence="ECO:0007829|PDB:2KCJ"
FT STRAND 43..45
FT /evidence="ECO:0007829|PDB:3RCP"
FT HELIX 46..48
FT /evidence="ECO:0007829|PDB:3RCP"
FT STRAND 50..52
FT /evidence="ECO:0007829|PDB:3RCP"
FT STRAND 58..65
FT /evidence="ECO:0007829|PDB:3RCP"
FT TURN 66..68
FT /evidence="ECO:0007829|PDB:3RCP"
FT STRAND 69..74
FT /evidence="ECO:0007829|PDB:3RCP"
FT HELIX 78..89
FT /evidence="ECO:0007829|PDB:3RCP"
SQ SEQUENCE 300 AA; 33861 MW; 0B6EF45C7D17E82C CRC64;
MEGVLYKWTN YLTGWQPRWF VLDNGILSYY DSQDDVCKGS KGSIKMAVCE IKVHSADNTR
MELIIPGEQH FYMKAVNAAE RQRWLVALGS SKACLTDTRT KKEKEISETS ESLKTKMSEL
RLYCDLLMQQ VHTIQEFVHH DENHSSPSAE NMNEASSLLS ATCNTFITTL EECVKIANAK
FKPEMFQLHH PDPLVSPVSP SPVQMMKRSV SHPGSCSSER SSHSIKEPVS TLHRLSQRRR
RTYSDTDSCS DIPLEDPDRP VHCSKNTLNG DLASATIPEE SRLMAKKQSE SEDTLPSFSS
