PI4KA_HUMAN
ID PI4KA_HUMAN Reviewed; 2102 AA.
AC P42356; Q7Z625; Q9UPG2;
DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
DT 17-FEB-2016, sequence version 4.
DT 03-AUG-2022, entry version 199.
DE RecName: Full=Phosphatidylinositol 4-kinase alpha;
DE Short=PI4-kinase alpha;
DE Short=PI4K-alpha;
DE Short=PtdIns-4-kinase alpha;
DE EC=2.7.1.67 {ECO:0000269|PubMed:10101268};
DE AltName: Full=Phosphatidylinositol 4-Kinase III alpha;
GN Name=PI4KA; Synonyms=PIK4, PIK4CA;
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] (ISOFORM 2), TISSUE SPECIFICITY, AND ACTIVITY
RP REGULATION.
RX PubMed=7961848; DOI=10.1016/s0021-9258(19)61989-7;
RA Wong K., Cantley L.C.;
RT "Cloning and characterization of a human phosphatidylinositol 4-kinase.";
RL J. Biol. Chem. 269:28878-28884(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=10591208; DOI=10.1038/990031;
RA Dunham I., Hunt A.R., Collins J.E., Bruskiewich R., Beare D.M., Clamp M.,
RA Smink L.J., Ainscough R., Almeida J.P., Babbage A.K., Bagguley C.,
RA Bailey J., Barlow K.F., Bates K.N., Beasley O.P., Bird C.P., Blakey S.E.,
RA Bridgeman A.M., Buck D., Burgess J., Burrill W.D., Burton J., Carder C.,
RA Carter N.P., Chen Y., Clark G., Clegg S.M., Cobley V.E., Cole C.G.,
RA Collier R.E., Connor R., Conroy D., Corby N.R., Coville G.J., Cox A.V.,
RA Davis J., Dawson E., Dhami P.D., Dockree C., Dodsworth S.J., Durbin R.M.,
RA Ellington A.G., Evans K.L., Fey J.M., Fleming K., French L., Garner A.A.,
RA Gilbert J.G.R., Goward M.E., Grafham D.V., Griffiths M.N.D., Hall C.,
RA Hall R.E., Hall-Tamlyn G., Heathcott R.W., Ho S., Holmes S., Hunt S.E.,
RA Jones M.C., Kershaw J., Kimberley A.M., King A., Laird G.K., Langford C.F.,
RA Leversha M.A., Lloyd C., Lloyd D.M., Martyn I.D., Mashreghi-Mohammadi M.,
RA Matthews L.H., Mccann O.T., Mcclay J., Mclaren S., McMurray A.A.,
RA Milne S.A., Mortimore B.J., Odell C.N., Pavitt R., Pearce A.V., Pearson D.,
RA Phillimore B.J.C.T., Phillips S.H., Plumb R.W., Ramsay H., Ramsey Y.,
RA Rogers L., Ross M.T., Scott C.E., Sehra H.K., Skuce C.D., Smalley S.,
RA Smith M.L., Soderlund C., Spragon L., Steward C.A., Sulston J.E.,
RA Swann R.M., Vaudin M., Wall M., Wallis J.M., Whiteley M.N., Willey D.L.,
RA Williams L., Williams S.A., Williamson H., Wilmer T.E., Wilming L.,
RA Wright C.L., Hubbard T., Bentley D.R., Beck S., Rogers J., Shimizu N.,
RA Minoshima S., Kawasaki K., Sasaki T., Asakawa S., Kudoh J., Shintani A.,
RA Shibuya K., Yoshizaki Y., Aoki N., Mitsuyama S., Roe B.A., Chen F., Chu L.,
RA Crabtree J., Deschamps S., Do A., Do T., Dorman A., Fang F., Fu Y., Hu P.,
RA Hua A., Kenton S., Lai H., Lao H.I., Lewis J., Lewis S., Lin S.-P., Loh P.,
RA Malaj E., Nguyen T., Pan H., Phan S., Qi S., Qian Y., Ray L., Ren Q.,
RA Shaull S., Sloan D., Song L., Wang Q., Wang Y., Wang Z., White J.,
RA Willingham D., Wu H., Yao Z., Zhan M., Zhang G., Chissoe S., Murray J.,
RA Miller N., Minx P., Fulton R., Johnson D., Bemis G., Bentley D.,
RA Bradshaw H., Bourne S., Cordes M., Du Z., Fulton L., Goela D., Graves T.,
RA Hawkins J., Hinds K., Kemp K., Latreille P., Layman D., Ozersky P.,
RA Rohlfing T., Scheet P., Walker C., Wamsley A., Wohldmann P., Pepin K.,
RA Nelson J., Korf I., Bedell J.A., Hillier L.W., Mardis E., Waterston R.,
RA Wilson R., Emanuel B.S., Shaikh T., Kurahashi H., Saitta S., Budarf M.L.,
RA McDermid H.E., Johnson A., Wong A.C.C., Morrow B.E., Edelmann L., Kim U.J.,
RA Shizuya H., Simon M.I., Dumanski J.P., Peyrard M., Kedra D., Seroussi E.,
RA Fransson I., Tapia I., Bruder C.E., O'Brien K.P., Wilkinson P.,
RA Bodenteich A., Hartman K., Hu X., Khan A.S., Lane L., Tilahun Y.,
RA Wright H.;
RT "The DNA sequence of human chromosome 22.";
RL Nature 402:489-495(1999).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 59-2102 (ISOFORM 1), FUNCTION, CATALYTIC
RP ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND TISSUE SPECIFICITY.
RX PubMed=10101268; DOI=10.1016/s1388-1981(99)00029-3;
RA Gehrmann T., Guelkan H., Suer S., Herberg F.W., Balla A., Vereb G. Jr.,
RA Mayr G.W., Heilmeyer L.M.G. Jr.;
RT "Functional expression and characterisation of a new human
RT phosphatidylinositol 4-kinase PI4K230.";
RL Biochim. Biophys. Acta 1437:341-356(1999).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1200-2102 (ISOFORM 1).
RC TISSUE=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 project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-265, AND IDENTIFICATION BY
RP 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 the
RT kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [6]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-257; SER-260; SER-262 AND
RP SER-265, AND 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 [7]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-265 AND SER-1436, AND
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 [9]
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., Buerckstuemmer T.,
RA 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 [10]
RP GENE STRUCTURE, FUNCTION, SUBCELLULAR LOCATION, IDENTIFICATION IN THE PI4K
RP COMPLEX, AND ACTIVITY REGULATION.
RX PubMed=23229899; DOI=10.1083/jcb.201206095;
RA Nakatsu F., Baskin J.M., Chung J., Tanner L.B., Shui G., Lee S.Y.,
RA Pirruccello M., Hao M., Ingolia N.T., Wenk M.R., De Camilli P.;
RT "PtdIns4P synthesis by PI4KIIIalpha at the plasma membrane and its impact
RT on plasma membrane identity.";
RL J. Cell Biol. 199:1003-1016(2012).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-230; SER-256; SER-257;
RP SER-262; SER-265; SER-429; TYR-1154 AND SER-1436, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and 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 [12]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH TTC7A.
RX PubMed=24417819; DOI=10.1053/j.gastro.2014.01.015;
RA Avitzur Y., Guo C., Mastropaolo L.A., Bahrami E., Chen H., Zhao Z.,
RA Elkadri A., Dhillon S., Murchie R., Fattouh R., Huynh H., Walker J.L.,
RA Wales P.W., Cutz E., Kakuta Y., Dudley J., Kammermeier J., Powrie F.,
RA Shah N., Walz C., Nathrath M., Kotlarz D., Puchaka J., Krieger J.R.,
RA Racek T., Kirchner T., Walters T.D., Brumell J.H., Griffiths A.M.,
RA Rezaei N., Rashtian P., Najafi M., Monajemzadeh M., Pelsue S.,
RA McGovern D.P., Uhlig H.H., Schadt E., Klein C., Snapper S.B., Muise A.M.;
RT "Mutations in tetratricopeptide repeat domain 7A result in a severe form of
RT very early onset inflammatory bowel disease.";
RL Gastroenterology 146:1028-1039(2014).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1436, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [14]
RP INVOLVEMENT IN NEDSPLB, VARIANTS NEDSPLB 796-ARG--TYR-2102 DEL AND
RP ASN-1854, AND CHARACTERIZATION OF VARIANT NEDSPLB ASN-1854.
RX PubMed=25855803; DOI=10.1093/hmg/ddv117;
RA Pagnamenta A.T., Howard M.F., Wisniewski E., Popitsch N., Knight S.J.,
RA Keays D.A., Quaghebeur G., Cox H., Cox P., Balla T., Taylor J.C., Kini U.;
RT "Germline recessive mutations in PI4KA are associated with perisylvian
RT polymicrogyria, cerebellar hypoplasia and arthrogryposis.";
RL Hum. Mol. Genet. 24:3732-3741(2015).
RN [15]
RP INTERACTION WITH TMEM150A, SUBCELLULAR LOCATION, AND ACTIVITY REGULATION.
RX PubMed=25608530; DOI=10.15252/embr.201439151;
RA Chung J., Nakatsu F., Baskin J.M., De Camilli P.;
RT "Plasticity of PI4KIIIalpha interactions at the plasma membrane.";
RL EMBO Rep. 16:312-320(2015).
RN [16]
RP IDENTIFICATION IN THE PI4K COMPLEX, AND ACTIVITY REGULATION.
RX PubMed=26571211; DOI=10.1038/ncb3271;
RA Baskin J.M., Wu X., Christiano R., Oh M.S., Schauder C.M., Gazzerro E.,
RA Messa M., Baldassari S., Assereto S., Biancheri R., Zara F., Minetti C.,
RA Raimondi A., Simons M., Walther T.C., Reinisch K.M., De Camilli P.;
RT "The leukodystrophy protein FAM126A (hyccin) regulates PtdIns(4)P synthesis
RT at the plasma membrane.";
RL Nat. Cell Biol. 18:132-138(2016).
RN [17]
RP IDENTIFICATION IN A COMPLEX WITH CHKA AND HCV NON-STRUCTURAL PROTEIN 5A
RP (MICROBIAL INFECTION).
RX PubMed=28566381; DOI=10.1128/jvi.00355-17;
RA Wong M.T., Chen S.S.;
RT "Hepatitis C Virus Subverts Human Choline Kinase-alpha To Bridge
RT Phosphatidylinositol-4-Kinase IIIalpha (PI4KIIIalpha) and NS5A and
RT Upregulates PI4KIIIalpha Activation, Thereby Promoting the Translocation of
RT the Ternary Complex to the Endoplasmic Reticulum for Viral Replication.";
RL J. Virol. 91:0-0(2017).
RN [18]
RP VARIANTS NEDSPLB TRP-119; ARG-472; 618-ARG--TYR-2102 DEL; LYS-1152;
RP THR-1198; ARG-1295; ASN-1664; ASN-1854; ARG-1925; SER-1987 AND THR-2041,
RP VARIANTS SPG84 MET-1556; ILE-1720 AND GLU-1820 DEL, INVOLVEMENT IN NEDSPLB,
RP AND INVOLVEMENT IN SPG84.
RX PubMed=34415322; DOI=10.1093/brain/awab124;
RA Verdura E., Rodriguez-Palmero A., Velez-Santamaria V., Planas-Serra L.,
RA de la Calle I., Raspall-Chaure M., Roubertie A., Benkirane M., Saettini F.,
RA Pavinato L., Mandrile G., O'Leary M., O'Heir E., Barredo E., Chacon A.,
RA Michaud V., Goizet C., Ruiz M., Schlueter A., Rouvet I., Sala-Coromina J.,
RA Fossati C., Iascone M., Canonico F., Marce-Grau A., de Souza P.,
RA Adams D.R., Casasnovas C., Rehm H.L., Mefford H.C.,
RA Gonzalez Gutierrez-Solana L., Brusco A., Koenig M., Macaya A., Pujol A.;
RT "Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with
RT hypomyelinating leukodystrophy.";
RL Brain 144:2659-2669(2021).
RN [19]
RP VARIANTS NEDSPLB 566-ARG--TYR-2102 DEL; PRO-777; 1191-GLN--TYR-2102 DEL;
RP TRP-1733; THR-1808; ASN-1854; GLU-1925 AND CYS-1937, VARIANT GIDID2
RP ASP-1623, CHARACTERIZATION OF VARIANT GIDID2 ASP-1623, INTERACTION WITH
RP TTC7A, INVOLVEMENT IN NEDSPLB, INVOLVEMENT IN GIDID2, AND MUTAGENESIS OF
RP ASP-1957.
RX PubMed=34415310; DOI=10.1093/brain/awab313;
RA Salter C.G., Cai Y., Lo B., Helman G., Taylor H., McCartney A.,
RA Leslie J.S., Accogli A., Zara F., Traverso M., Fasham J., Lees J.A.,
RA Ferla M.P., Chioza B.A., Wenger O., Scott E., Cross H.E., Crawford J.,
RA Warshawsky I., Keisling M., Agamanolis D., Ward Melver C., Cox H.,
RA Elawad M., Marton T., Wakeling M.N., Holzinger D., Tippelt S., Munteanu M.,
RA Valcheva D., Deal C., Van Meerbeke S., Walsh Vockley C., Butte M.J.,
RA Acar U., van der Knaap M.S., Korenke G.C., Kotzaeridou U., Balla T.,
RA Simons C., Uhlig H.H., Crosby A.H., De Camilli P., Wolf N.I., Baple E.L.;
RT "Biallelic PI4KA variants cause neurological, intestinal and immunological
RT disease.";
RL Brain 144:3597-3610(2021).
CC -!- FUNCTION: Acts on phosphatidylinositol (PtdIns) in the first committed
CC step in the production of the second messenger inositol-1,4,5,-
CC trisphosphate. {ECO:0000269|PubMed:10101268,
CC ECO:0000269|PubMed:23229899}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol) + ATP = a
CC 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol 4-phosphate) + ADP +
CC H(+); Xref=Rhea:RHEA:19877, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:57880, ChEBI:CHEBI:58178, ChEBI:CHEBI:456216;
CC EC=2.7.1.67; Evidence={ECO:0000269|PubMed:10101268};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:19878;
CC Evidence={ECO:0000305|PubMed:7961848};
CC -!- ACTIVITY REGULATION: Activated by Triton X-100, insensitive to
CC inhibition by adenosine and inhibited by wortmannin (By similarity).
CC Isoform 2 is activated by detergents such as Triton X-100 and inhibited
CC by adenosine (PubMed:7961848). The PI4K complex acts as a regulator of
CC phosphatidylinositol 4-phosphate (PtdIns(4)P) synthesis
CC (PubMed:23229899, PubMed:26571211). Interaction with TMEM150A regulates
CC PtdIns(4)P synthesis (PubMed:25608530). {ECO:0000250|UniProtKB:O08662,
CC ECO:0000269|PubMed:23229899, ECO:0000269|PubMed:25608530,
CC ECO:0000269|PubMed:26571211, ECO:0000269|PubMed:7961848}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=300 uM for ATP {ECO:0000269|PubMed:10101268};
CC -!- SUBUNIT: Component of a phosphatidylinositol 4-kinase (PI4K) complex,
CC composed of PI4KA, EFR3 (EFR3A or EFR3B), TTC7 (TTC7A or TTC7B) and
CC FAM126 (FAM126A or FAM126B) (PubMed:23229899, PubMed:24417819,
CC PubMed:26571211, PubMed:34415310). Interacts with TMEM150A; regulating
CC recruitment to the plasma membrane (PubMed:25608530). Interacts with
CC TTC7A (PubMed:34415310). {ECO:0000269|PubMed:23229899,
CC ECO:0000269|PubMed:24417819, ECO:0000269|PubMed:25608530,
CC ECO:0000269|PubMed:26571211, ECO:0000269|PubMed:34415310}.
CC -!- SUBUNIT: (Microbial infection) Interacts with CHKA/Choline Kinase-
CC alpha; CHKA bridges PI4KA and hepatitis C virus (HCV) non-structural
CC protein 5A (NS5A) and potentiates NS5A-stimulated PI4KA activity, which
CC then facilitates the targeting of the ternary complex to the ER for
CC viral replication. {ECO:0000269|PubMed:28566381}.
CC -!- INTERACTION:
CC P42356; PRO_0000037576 [P27958]; Xeno; NbExp=7; IntAct=EBI-723050, EBI-8753518;
CC P42356; PRO_0000045602 [Q99IB8]; Xeno; NbExp=5; IntAct=EBI-723050, EBI-6927873;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:23229899,
CC ECO:0000269|PubMed:24417819}. Cell membrane
CC {ECO:0000269|PubMed:23229899, ECO:0000269|PubMed:24417819}.
CC Note=Localization to the plasma membrane is mediated by the PI4K
CC complex and association with EFR3 (EFR3A or EFR3B), TTC7 (TTC7A or
CC TTC7B) and FAM126 (FAM126A or FAM126B) (PubMed:23229899). Localization
CC to the plasma membrane is regulated by TMEM150A (PubMed:25608530).
CC {ECO:0000269|PubMed:23229899, ECO:0000269|PubMed:25608530}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=PI4K230 {ECO:0000303|PubMed:10101268};
CC IsoId=P42356-1; Sequence=Displayed;
CC Name=2; Synonyms=PI4K97 {ECO:0000303|PubMed:10101268};
CC IsoId=P42356-2; Sequence=VSP_008805;
CC -!- TISSUE SPECIFICITY: Expressed ubiquitously. Highest levels in placenta
CC and brain. Little or no expression in lung, liver, pancreas, testis or
CC leukocytes. {ECO:0000269|PubMed:10101268, ECO:0000269|PubMed:7961848}.
CC -!- DISEASE: Neurodevelopmental disorder with spasticity, hypomyelinating
CC leukodystrophy, and brain abnormalities (NEDSPLB) [MIM:616531]: A
CC severe autosomal recessive disorder characterized by global
CC developmental delay with impaired intellectual development and poor or
CC absent speech, axial hypotonia, and peripheral spasticity and
CC hyperreflexia. Brain imaging shows hypomyelination with decreased white
CC matter volume, cerebral and cerebellar atrophy, and thin corpus
CC callosum. Polymicrogyria may be observed in rare cases. Some patients
CC have a primary immunodeficiency or gastrointestinal disturbances
CC similar to inflammatory bowel disease. {ECO:0000269|PubMed:25855803,
CC ECO:0000269|PubMed:34415310, ECO:0000269|PubMed:34415322}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- DISEASE: Gastrointestinal defects and immunodeficiency syndrome 2
CC (GIDID2) [MIM:619708]: A severe autosomal recessive disorder
CC characterized by multiple intestinal atresia apparent soon after birth.
CC Affected infants have a distended abdomen, bowel obstruction and do not
CC pass meconium. There is some evidence of inflammatory bowel disease.
CC Death occurs in the first weeks of life. Some patients may also have
CC immunodeficiency. {ECO:0000269|PubMed:34415310}. Note=The disease is
CC caused by variants affecting the gene represented in this entry.
CC -!- DISEASE: Spastic paraplegia 84, autosomal recessive (SPG84)
CC [MIM:619621]: A form of spastic paraplegia, a neurodegenerative
CC disorder characterized by a slow, gradual, progressive weakness and
CC spasticity of the lower limbs. Rate of progression and the severity of
CC symptoms are quite variable. Initial symptoms may include difficulty
CC with balance, weakness and stiffness in the legs, muscle spasms, and
CC dragging the toes when walking. In some forms of the disorder, bladder
CC symptoms (such as incontinence) may appear, or the weakness and
CC stiffness may spread to other parts of the body. SPG84 is characterized
CC by onset of slowly progressive walking difficulties due to lower limb
CC weakness, stiffness, and spasticity in the first 2 decades of life.
CC {ECO:0000269|PubMed:34415322}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the PI3/PI4-kinase family. Type III PI4K
CC subfamily. {ECO:0000305}.
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DR EMBL; L36151; AAA56839.1; -; mRNA.
DR EMBL; AC007050; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC007308; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AF012872; AAD13352.1; -; mRNA.
DR EMBL; BC018120; AAH18120.2; -; mRNA.
DR EMBL; BC053654; AAH53654.1; -; mRNA.
DR CCDS; CCDS33603.2; -. [P42356-1]
DR PIR; A55404; A55404.
DR RefSeq; NP_477352.3; NM_058004.3. [P42356-1]
DR PDB; 6BQ1; EM; 3.60 A; A/E=932-2102.
DR PDBsum; 6BQ1; -.
DR AlphaFoldDB; P42356; -.
DR SMR; P42356; -.
DR CORUM; P42356; -.
DR IntAct; P42356; 89.
DR MINT; P42356; -.
DR STRING; 9606.ENSP00000255882; -.
DR BindingDB; P42356; -.
DR ChEMBL; CHEMBL3667; -.
DR DrugCentral; P42356; -.
DR GuidetoPHARMACOLOGY; 2148; -.
DR SwissLipids; SLP:000000895; -.
DR SwissLipids; SLP:000000902; -. [P42356-2]
DR iPTMnet; P42356; -.
DR MetOSite; P42356; -.
DR PhosphoSitePlus; P42356; -.
DR SwissPalm; P42356; -.
DR BioMuta; PI4KA; -.
DR DMDM; 218512114; -.
DR EPD; P42356; -.
DR jPOST; P42356; -.
DR MassIVE; P42356; -.
DR MaxQB; P42356; -.
DR PaxDb; P42356; -.
DR PeptideAtlas; P42356; -.
DR PRIDE; P42356; -.
DR ProteomicsDB; 55512; -. [P42356-1]
DR ProteomicsDB; 55513; -. [P42356-2]
DR Antibodypedia; 34781; 55 antibodies from 19 providers.
DR DNASU; 5297; -.
DR Ensembl; ENST00000255882.11; ENSP00000255882.6; ENSG00000241973.11. [P42356-1]
DR GeneID; 5297; -.
DR KEGG; hsa:5297; -.
DR MANE-Select; ENST00000255882.11; ENSP00000255882.6; NM_058004.4; NP_477352.3.
DR CTD; 5297; -.
DR DisGeNET; 5297; -.
DR GeneCards; PI4KA; -.
DR HGNC; HGNC:8983; PI4KA.
DR HPA; ENSG00000241973; Low tissue specificity.
DR MalaCards; PI4KA; -.
DR MIM; 600286; gene.
DR MIM; 616531; phenotype.
DR MIM; 619621; phenotype.
DR MIM; 619708; phenotype.
DR neXtProt; NX_P42356; -.
DR OpenTargets; ENSG00000241973; -.
DR Orphanet; 98889; Bilateral perisylvian polymicrogyria.
DR Orphanet; 436252; Combined immunodeficiency-enteropathy spectrum.
DR PharmGKB; PA162399305; -.
DR VEuPathDB; HostDB:ENSG00000241973; -.
DR eggNOG; KOG0902; Eukaryota.
DR GeneTree; ENSGT00550000074798; -.
DR InParanoid; P42356; -.
DR OMA; QEYRYSE; -.
DR OrthoDB; 1147978at2759; -.
DR PhylomeDB; P42356; -.
DR TreeFam; TF102041; -.
DR BioCyc; MetaCyc:HS13481-MON; -.
DR PathwayCommons; P42356; -.
DR Reactome; R-HSA-1483248; Synthesis of PIPs at the ER membrane.
DR Reactome; R-HSA-1660514; Synthesis of PIPs at the Golgi membrane.
DR SABIO-RK; P42356; -.
DR SignaLink; P42356; -.
DR BioGRID-ORCS; 5297; 430 hits in 1091 CRISPR screens.
DR ChiTaRS; PI4KA; human.
DR GeneWiki; PI4KA; -.
DR GenomeRNAi; 5297; -.
DR Pharos; P42356; Tchem.
DR PRO; PR:P42356; -.
DR Proteomes; UP000005640; Chromosome 22.
DR RNAct; P42356; protein.
DR Bgee; ENSG00000241973; Expressed in superior frontal gyrus and 94 other tissues.
DR ExpressionAtlas; P42356; baseline and differential.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0005925; C:focal adhesion; HDA:UniProtKB.
DR GO; GO:0030660; C:Golgi-associated vesicle membrane; ISS:UniProtKB.
DR GO; GO:0016020; C:membrane; HDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0004430; F:1-phosphatidylinositol 4-kinase activity; ISS:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0045296; F:cadherin binding; HDA:BHF-UCL.
DR GO; GO:0016301; F:kinase activity; IDA:MGI.
DR GO; GO:0052742; F:phosphatidylinositol kinase activity; IBA:GO_Central.
DR GO; GO:0044788; P:modulation by host of viral process; IMP:ParkinsonsUK-UCL.
DR GO; GO:0006661; P:phosphatidylinositol biosynthetic process; TAS:Reactome.
DR GO; GO:0046854; P:phosphatidylinositol phosphate biosynthetic process; ISS:UniProtKB.
DR GO; GO:0048015; P:phosphatidylinositol-mediated signaling; IBA:GO_Central.
DR GO; GO:0016310; P:phosphorylation; IDA:MGI.
DR GO; GO:0140754; P:reorganization of cellular membranes to establish viral sites of replication; IMP:ParkinsonsUK-UCL.
DR GO; GO:0007165; P:signal transduction; NAS:ProtInc.
DR Gene3D; 1.10.1070.11; -; 1.
DR Gene3D; 1.25.40.70; -; 1.
DR InterPro; IPR016024; ARM-type_fold.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000403; PI3/4_kinase_cat_dom.
DR InterPro; IPR036940; PI3/4_kinase_cat_sf.
DR InterPro; IPR018936; PI3/4_kinase_CS.
DR InterPro; IPR001263; PI3K_accessory_dom.
DR InterPro; IPR042236; PI3K_accessory_sf.
DR InterPro; IPR045495; PI4K_N.
DR InterPro; IPR015433; PI_Kinase.
DR PANTHER; PTHR10048; PTHR10048; 1.
DR Pfam; PF00454; PI3_PI4_kinase; 1.
DR Pfam; PF00613; PI3Ka; 1.
DR Pfam; PF19274; PI4K_N; 1.
DR SMART; SM00145; PI3Ka; 1.
DR SMART; SM00146; PI3Kc; 1.
DR SUPFAM; SSF48371; SSF48371; 2.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS00915; PI3_4_KINASE_1; 1.
DR PROSITE; PS00916; PI3_4_KINASE_2; 1.
DR PROSITE; PS50290; PI3_4_KINASE_3; 1.
DR PROSITE; PS51545; PIK_HELICAL; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; ATP-binding; Cell membrane; Cytoplasm;
KW Disease variant; Hereditary spastic paraplegia; Kinase; Lipid metabolism;
KW Membrane; Neurodegeneration; Nucleotide-binding; Phosphoprotein;
KW Reference proteome; Transferase.
FT CHAIN 1..2102
FT /note="Phosphatidylinositol 4-kinase alpha"
FT /id="PRO_0000088827"
FT DOMAIN 1530..1718
FT /note="PIK helical"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00878"
FT DOMAIN 1808..2086
FT /note="PI3K/PI4K catalytic"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00269"
FT REGION 1814..1820
FT /note="G-loop"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00269"
FT REGION 1954..1962
FT /note="Catalytic loop"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00269"
FT REGION 1973..1997
FT /note="Activation loop"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00269"
FT MOD_RES 230
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 256
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 257
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 259
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:E9Q3L2"
FT MOD_RES 260
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648"
FT MOD_RES 262
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 265
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:18691976, ECO:0007744|PubMed:19690332,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 429
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 1154
FT /note="Phosphotyrosine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 1436
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19690332,
FT ECO:0007744|PubMed:23186163, ECO:0007744|PubMed:24275569"
FT VAR_SEQ 1..1248
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:7961848"
FT /id="VSP_008805"
FT VARIANT 119
FT /note="R -> W (in NEDSPLB; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:34415322"
FT /id="VAR_086468"
FT VARIANT 380
FT /note="M -> V (in dbSNP:rs17819211)"
FT /id="VAR_050531"
FT VARIANT 472
FT /note="S -> R (in NEDSPLB; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:34415322"
FT /id="VAR_086469"
FT VARIANT 566..2102
FT /note="Missing (in NEDSPLB)"
FT /evidence="ECO:0000269|PubMed:34415310"
FT /id="VAR_086470"
FT VARIANT 618..2102
FT /note="Missing (in NEDSPLB)"
FT /evidence="ECO:0000269|PubMed:34415322"
FT /id="VAR_086471"
FT VARIANT 777
FT /note="L -> P (in NEDSPLB)"
FT /evidence="ECO:0000269|PubMed:34415310"
FT /id="VAR_086472"
FT VARIANT 796..2102
FT /note="Missing (in NEDSPLB)"
FT /evidence="ECO:0000269|PubMed:25855803"
FT /id="VAR_086473"
FT VARIANT 1152
FT /note="E -> K (in NEDSPLB; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:34415322"
FT /id="VAR_086474"
FT VARIANT 1191..2102
FT /note="Missing (in NEDSPLB)"
FT /evidence="ECO:0000269|PubMed:34415310"
FT /id="VAR_086475"
FT VARIANT 1198
FT /note="A -> T (in NEDSPLB; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:34415322"
FT /id="VAR_086476"
FT VARIANT 1295
FT /note="H -> R (in NEDSPLB; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:34415322"
FT /id="VAR_086477"
FT VARIANT 1556
FT /note="V -> M (in SPG84; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:34415322"
FT /id="VAR_086478"
FT VARIANT 1623
FT /note="Y -> D (in GIDID2; decreased interaction with TTC7A
FT resulting in reduced PI4K complex stability; no effect on
FT kinase activity)"
FT /evidence="ECO:0000269|PubMed:34415310"
FT /id="VAR_086479"
FT VARIANT 1664
FT /note="D -> N (in NEDSPLB)"
FT /evidence="ECO:0000269|PubMed:34415322"
FT /id="VAR_086480"
FT VARIANT 1720
FT /note="T -> I (in SPG84; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:34415322"
FT /id="VAR_086481"
FT VARIANT 1733
FT /note="R -> W (in NEDSPLB; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:34415310"
FT /id="VAR_086482"
FT VARIANT 1808
FT /note="K -> T (in NEDSPLB)"
FT /evidence="ECO:0000269|PubMed:34415310"
FT /id="VAR_086483"
FT VARIANT 1820
FT /note="Missing (in SPG84; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:34415322"
FT /id="VAR_086484"
FT VARIANT 1851
FT /note="V -> L (in dbSNP:rs2539908)"
FT /id="VAR_059549"
FT VARIANT 1854
FT /note="D -> N (in NEDSPLB; loss of kinase activity; no
FT effect on protein abundance; dbSNP:rs747119727)"
FT /evidence="ECO:0000269|PubMed:25855803,
FT ECO:0000269|PubMed:34415310, ECO:0000269|PubMed:34415322"
FT /id="VAR_074640"
FT VARIANT 1925
FT /note="G -> E (in NEDSPLB)"
FT /evidence="ECO:0000269|PubMed:34415310"
FT /id="VAR_086485"
FT VARIANT 1925
FT /note="G -> R (in NEDSPLB; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:34415322"
FT /id="VAR_086486"
FT VARIANT 1937
FT /note="Y -> C (in NEDSPLB)"
FT /evidence="ECO:0000269|PubMed:34415310"
FT /id="VAR_086487"
FT VARIANT 1987
FT /note="N -> S (in NEDSPLB; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:34415322"
FT /id="VAR_086488"
FT VARIANT 2041
FT /note="M -> T (in NEDSPLB; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:34415322"
FT /id="VAR_086489"
FT MUTAGEN 1957
FT /note="D->A: Loss of kinase activity."
FT /evidence="ECO:0000269|PubMed:34415310"
FT CONFLICT 438
FT /note="N -> S (in Ref. 3; AAD13352)"
FT /evidence="ECO:0000305"
FT CONFLICT 1947
FT /note="S -> I (in Ref. 4; AAH53654)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 2102 AA; 236830 MW; ED4C3C9EA79E6B5D CRC64;
MAAAPARGGG GGGGGGGGCS GSGSSASRGF YFNTVLSLAR SLAVQRPASL EKVQKLLCMC
PVDFHGIFQL DERRRDAVIA LGIFLIESDL QHKDCVVPYL LRLLKGLPKV YWVEESTARK
GRGALPVAES FSFCLVTLLS DVAYRDPSLR DEILEVLLQV LHVLLGMCQA LEIQDKEYLC
KYAIPCLIGI SRAFGRYSNM EESLLSKLFP KIPPHSLRVL EELEGVRRRS FNDFRSILPS
NLLTVCQEGT LKRKTSSVSS ISQVSPERGM PPPSSPGGSA FHYFEASCLP DGTALEPEYY
FSTISSSFSV SPLFNGVTYK EFNIPLEMLR ELLNLVKKIV EEAVLKSLDA IVASVMEANP
SADLYYTSFS DPLYLTMFKM LRDTLYYMKD LPTSFVKEIH DFVLEQFNTS QGELQKILHD
ADRIHNELSP LKLRCQANAA CVDLMVWAVK DEQGAENLCI KLSEKLQSKT SSKVIIAHLP
LLICCLQGLG RLCERFPVVV HSVTPSLRDF LVIPSPVLVK LYKYHSQYHT VAGNDIKISV
TNEHSESTLN VMSGKKSQPS MYEQLRDIAI DNICRCLKAG LTVDPVIVEA FLASLSNRLY
ISQESDKDAH LIPDHTIRAL GHIAVALRDT PKVMEPILQI LQQKFCQPPS PLDVLIIDQL
GCLVITGNQY IYQEVWNLFQ QISVKASSVV YSATKDYKDH GYRHCSLAVI NALANIAANI
QDEHLVDELL MNLLELFVQL GLEGKRASER ASEKGPALKA SSSAGNLGVL IPVIAVLTRR
LPPIKEAKPR LQKLFRDFWL YSVLMGFAVE GSGLWPEEWY EGVCEIATKS PLLTFPSKEP
LRSVLQYNSA MKNDTVTPAE LSELRSTIIN LLDPPPEVSA LINKLDFAMS TYLLSVYRLE
YMRVLRSTDP DRFQVMFCYF EDKAIQKDKS GMMQCVIAVA DKVFDAFLNM MADKAKTKEN
EEELERHAQF LLVNFNHIHK RIRRVADKYL SGLVDKFPHL LWSGTVLKTM LDILQTLSLS
LSADIHKDQP YYDIPDAPYR ITVPDTYEAR ESIVKDFAAR CGMILQEAMK WAPTVTKSHL
QEYLNKHQNW VSGLSQHTGL AMATESILHF AGYNKQNTTL GATQLSERPA CVKKDYSNFM
ASLNLRNRYA GEVYGMIRFS GTTGQMSDLN KMMVQDLHSA LDRSHPQHYT QAMFKLTAML
ISSKDCDPQL LHHLCWGPLR MFNEHGMETA LACWEWLLAG KDGVEVPFMR EMAGAWHMTV
EQKFGLFSAE IKEADPLAAS EASQPKPCPP EVTPHYIWID FLVQRFEIAK YCSSDQVEIF
SSLLQRSMSL NIGGAKGSMN RHVAAIGPRF KLLTLGLSLL HADVVPNATI RNVLREKIYS
TAFDYFSCPP KFPTQGEKRL REDISIMIKF WTAMFSDKKY LTASQLVPPD NQDTRSNLDI
TVGSRQQATQ GWINTYPLSS GMSTISKKSG MSKKTNRGSQ LHKYYMKRRT LLLSLLATEI
ERLITWYNPL SAPELELDQA GENSVANWRS KYISLSEKQW KDNVNLAWSI SPYLAVQLPA
RFKNTEAIGN EVTRLVRLDP GAVSDVPEAI KFLVTWHTID ADAPELSHVL CWAPTDPPTG
LSYFSSMYPP HPLTAQYGVK VLRSFPPDAI LFYIPQIVQA LRYDKMGYVR EYILWAASKS
QLLAHQFIWN MKTNIYLDEE GHQKDPDIGD LLDQLVEEIT GSLSGPAKDF YQREFDFFNK
ITNVSAIIKP YPKGDERKKA CLSALSEVKV QPGCYLPSNP EAIVLDIDYK SGTPMQSAAK
APYLAKFKVK RCGVSELEKE GLRCRSDSED ECSTQEADGQ KISWQAAIFK VGDDCRQDML
ALQIIDLFKN IFQLVGLDLF VFPYRVVATA PGCGVIECIP DCTSRDQLGR QTDFGMYDYF
TRQYGDESTL AFQQARYNFI RSMAAYSLLL FLLQIKDRHN GNIMLDKKGH IIHIDFGFMF
ESSPGGNLGW EPDIKLTDEM VMIMGGKMEA TPFKWFMEMC VRGYLAVRPY MDAVVSLVTL
MLDTGLPCFR GQTIKLLKHR FSPNMTEREA ANFIMKVIQS CFLSNRSRTY DMIQYYQNDI
PY
