PP2AA_HUMAN
ID PP2AA_HUMAN Reviewed; 309 AA.
AC P67775; P05323; P13197;
DT 11-OCT-2004, integrated into UniProtKB/Swiss-Prot.
DT 11-OCT-2004, sequence version 1.
DT 03-AUG-2022, entry version 178.
DE RecName: Full=Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform;
DE Short=PP2A-alpha;
DE EC=3.1.3.16 {ECO:0000269|PubMed:1848668, ECO:0000269|PubMed:30595372, ECO:0000269|PubMed:30611118};
DE AltName: Full=Replication protein C;
DE Short=RP-C;
GN Name=PPP2CA;
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 1).
RC TISSUE=Fibroblast;
RX PubMed=2849764; DOI=10.1093/nar/16.23.11365;
RA Stone S.R., Mayer R., Wernet W., Maurer F., Hofsteenge J., Hemmings B.A.;
RT "The nucleotide sequence of the cDNA encoding the human lung protein
RT phosphatase 2A alpha catalytic subunit.";
RL Nucleic Acids Res. 16:11365-11365(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Liver;
RX PubMed=2837763; DOI=10.1073/pnas.85.12.4252;
RA Arino J., Woon C.W., Brautigan D.L., Miller T.B. Jr., Johnson G.L.;
RT "Human liver phosphatase 2A: cDNA and amino acid sequence of two catalytic
RT subunit isotypes.";
RL Proc. Natl. Acad. Sci. U.S.A. 85:4252-4256(1988).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=1846293; DOI=10.1021/bi00215a014;
RA Khew-Goodall Y., Mayer R.E., Maurer F., Stone S.R., Hemmings B.A.;
RT "Structure and transcriptional regulation of protein phosphatase 2A
RT catalytic subunit genes.";
RL Biochemistry 30:89-97(1991).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Lung, Placenta, 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 project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP DEPHOSPHORYLATION OF SV40 LARGE-T ANTIGEN AND P53 PROTEIN, AND CATALYTIC
RP ACTIVITY.
RX PubMed=1848668; DOI=10.1128/mcb.11.4.1996-2003.1991;
RA Scheidtmann K.H., Mumby M.C., Rundell K., Walter G.;
RT "Dephosphorylation of simian virus 40 large-T antigen and p53 protein by
RT protein phosphatase 2A: inhibition by small-t antigen.";
RL Mol. Cell. Biol. 11:1996-2003(1991).
RN [6]
RP METHYLATION AT LEU-309.
RX PubMed=8206937; DOI=10.1016/s0021-9258(17)34009-7;
RA Favre B., Zolnierowicz S., Turowski P., Hemmings B.A.;
RT "The catalytic subunit of protein phosphatase 2A is carboxyl-methylated in
RT vivo.";
RL J. Biol. Chem. 269:16311-16317(1994).
RN [7]
RP INTERACTION WITH IGBP1.
RX PubMed=9647778; DOI=10.1006/bbrc.1998.8792;
RA Chen J., Peterson R.T., Schreiber S.L.;
RT "Alpha 4 associates with protein phosphatases 2A, 4, and 6.";
RL Biochem. Biophys. Res. Commun. 247:827-832(1998).
RN [8]
RP MUTAGENESIS OF LEU-309.
RX PubMed=10191253; DOI=10.1042/bj3390241;
RA Bryant J.C., Westphal R.S., Wadzinski B.E.;
RT "Methylated C-terminal leucine residue of PP2A catalytic subunit is
RT important for binding of regulatory Balpha subunit.";
RL Biochem. J. 339:241-246(1999).
RN [9]
RP PARTIAL PROTEIN SEQUENCE, AND ACTIVATION OF SV40 REPLICATION.
RX PubMed=2555176; DOI=10.1002/j.1460-2075.1989.tb08568.x;
RA Virshup D.M., Kauffman M.G., Kelly T.J.;
RT "Activation of SV40 DNA replication in vitro by cellular protein
RT phosphatase 2A.";
RL EMBO J. 8:3891-3898(1989).
RN [10]
RP INTERACTION WITH AXIN1, AND FUNCTION.
RX PubMed=9920888; DOI=10.1074/jbc.274.6.3439;
RA Hsu W., Zeng L., Costantini F.;
RT "Identification of a domain of Axin that binds to the serine/threonine
RT protein phosphatase 2A and a self-binding domain.";
RL J. Biol. Chem. 274:3439-3445(1999).
RN [11]
RP FUNCTION, AND INTERACTION WITH RAF1.
RX PubMed=10801873; DOI=10.1074/jbc.m003259200;
RA Abraham D., Podar K., Pacher M., Kubicek M., Welzel N., Hemmings B.A.,
RA Dilworth S.M., Mischak H., Kolch W., Baccarini M.;
RT "Raf-1-associated protein phosphatase 2A as a positive regulator of kinase
RT activation.";
RL J. Biol. Chem. 275:22300-22304(2000).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY, AND INTERACTION WITH SGO1.
RX PubMed=16580887; DOI=10.1016/j.devcel.2006.03.010;
RA Tang Z., Shu H., Qi W., Mahmood N.A., Mumby M.C., Yu H.;
RT "PP2A is required for centromeric localization of Sgo1 and proper
RT chromosome segregation.";
RL Dev. Cell 10:575-585(2006).
RN [13]
RP INTERACTION WITH ADCY8.
RX PubMed=16258073; DOI=10.1124/mol.105.018275;
RA Crossthwaite A.J., Ciruela A., Rayner T.F., Cooper D.M.;
RT "A direct interaction between the N terminus of adenylyl cyclase AC8 and
RT the catalytic subunit of protein phosphatase 2A.";
RL Mol. Pharmacol. 69:608-617(2006).
RN [14]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH SGO1.
RX PubMed=16541025; DOI=10.1038/nature04663;
RA Kitajima T.S., Sakuno T., Ishiguro K., Iemura S., Natsume T.,
RA Kawashima S.A., Watanabe Y.;
RT "Shugoshin collaborates with protein phosphatase 2A to protect cohesin.";
RL Nature 441:46-52(2006).
RN [15]
RP INTERACTION WITH PIM3.
RX PubMed=12473674; DOI=10.1074/jbc.m208246200;
RA Losman J.A., Chen X.P., Vuong B.Q., Fay S., Rothman P.B.;
RT "Protein phosphatase 2A regulates the stability of Pim protein kinases.";
RL J. Biol. Chem. 278:4800-4805(2003).
RN [16]
RP FUNCTION, AND INTERACTION WITH TP53.
RX PubMed=17245430; DOI=10.1038/sj.emboj.7601519;
RA Li H.H., Cai X., Shouse G.P., Piluso L.G., Liu X.;
RT "A specific PP2A regulatory subunit, B56gamma, mediates DNA damage-induced
RT dephosphorylation of p53 at Thr55.";
RL EMBO J. 26:402-411(2007).
RN [17]
RP INTERACTION WITH SGO2.
RX PubMed=17485487; DOI=10.1083/jcb.200701122;
RA Huang H., Feng J., Famulski J., Rattner J.B., Liu S.T., Kao G.D.,
RA Muschel R., Chan G.K., Yen T.J.;
RT "Tripin/hSgo2 recruits MCAK to the inner centromere to correct defective
RT kinetochore attachments.";
RL J. Cell Biol. 177:413-424(2007).
RN [18]
RP INTERACTION WITH SPRY2.
RX PubMed=17974561; DOI=10.1074/jbc.m705457200;
RA Chandramouli S., Yu C.Y., Yusoff P., Lao D.H., Leong H.F., Mizuno K.,
RA Guy G.R.;
RT "Tesk1 interacts with Spry2 to abrogate its inhibition of ERK
RT phosphorylation downstream of receptor tyrosine kinase signaling.";
RL J. Biol. Chem. 283:1679-1691(2008).
RN [19]
RP INTERACTION WITH IGBP1.
RX PubMed=19818709; DOI=10.1016/j.molcel.2009.09.025;
RA Kong M., Ditsworth D., Lindsten T., Thompson C.B.;
RT "Alpha4 is an essential regulator of PP2A phosphatase activity.";
RL Mol. Cell 36:51-60(2009).
RN [20]
RP INTERACTION WITH IGBP1.
RX PubMed=20092282; DOI=10.1021/bi901837h;
RA McConnell J.L., Watkins G.R., Soss S.E., Franz H.S., McCorvey L.R.,
RA Spiller B.W., Chazin W.J., Wadzinski B.E.;
RT "Alpha4 is a ubiquitin-binding protein that regulates protein
RT serine/threonine phosphatase 2A ubiquitination.";
RL Biochemistry 49:1713-1718(2010).
RN [21]
RP INTERACTION WITH GSK3B.
RX PubMed=20080667; DOI=10.1073/pnas.0908133107;
RA Xie D., Gore C., Liu J., Pong R.C., Mason R., Hao G., Long M., Kabbani W.,
RA Yu L., Zhang H., Chen H., Sun X., Boothman D.A., Min W., Hsieh J.T.;
RT "Role of DAB2IP in modulating epithelial-to-mesenchymal transition and
RT prostate cancer metastasis.";
RL Proc. Natl. Acad. Sci. U.S.A. 107:2485-2490(2010).
RN [22]
RP ALTERNATIVE SPLICING (ISOFORM 2).
RX PubMed=22167190; DOI=10.1074/jbc.m111.283341;
RA Migueleti D.L., Smetana J.H., Nunes H.F., Kobarg J., Zanchin N.I.;
RT "Identification and characterization of an alternatively spliced isoform of
RT the human protein phosphatase 2Aalpha catalytic subunit.";
RL J. Biol. Chem. 287:4853-4862(2012).
RN [23]
RP FUNCTION.
RX PubMed=22613722; DOI=10.1074/jbc.m112.368613;
RA Watkins G.R., Wang N., Mazalouskas M.D., Gomez R.J., Guthrie C.R.,
RA Kraemer B.C., Schweiger S., Spiller B.W., Wadzinski B.E.;
RT "Monoubiquitination promotes calpain cleavage of the protein phosphatase 2A
RT (PP2A) regulatory subunit alpha4, altering PP2A stability and microtubule-
RT associated protein phosphorylation.";
RL J. Biol. Chem. 287:24207-24215(2012).
RN [24]
RP INTERACTION WITH BECN1 AND AMBRA1.
RX PubMed=25803737; DOI=10.1080/15384101.2015.1021526;
RA Cianfanelli V., D'Orazio M., Cecconi F.;
RT "AMBRA1 and BECLIN 1 interplay in the crosstalk between autophagy and cell
RT proliferation.";
RL Cell Cycle 14:959-963(2015).
RN [25]
RP FUNCTION, AND INTERACTION WITH AMBRA1.
RX PubMed=25438055; DOI=10.1038/ncb3072;
RA Cianfanelli V., Fuoco C., Lorente M., Salazar M., Quondamatteo F.,
RA Gherardini P.F., De Zio D., Nazio F., Antonioli M., D'Orazio M., Skobo T.,
RA Bordi M., Rohde M., Dalla Valle L., Helmer-Citterich M., Gretzmeier C.,
RA Dengjel J., Fimia G.M., Piacentini M., Di Bartolomeo S., Velasco G.,
RA Cecconi F.;
RT "AMBRA1 links autophagy to cell proliferation and tumorigenesis by
RT promoting c-Myc dephosphorylation and degradation.";
RL Nat. Cell Biol. 17:20-30(2015).
RN [26]
RP INTERACTION WITH PABIR1, UBIQUITINATION, AND PROTEASOMAL DEGRADATION.
RX PubMed=27588481; DOI=10.18632/oncotarget.11698;
RA Fan L., Liu M.H., Guo M., Hu C.X., Yan Z.W., Chen J., Chen G.Q., Huang Y.;
RT "FAM122A, a new endogenous inhibitor of protein phosphatase 2A.";
RL Oncotarget 7:63887-63900(2016).
RN [27]
RP INTERACTION WITH MFHAS1.
RX PubMed=28609714; DOI=10.1016/j.molimm.2017.06.017;
RA Shi Q., Xiong B., Zhong J., Wang H., Ma D., Miao C.;
RT "MFHAS1 suppresses TLR4 signaling pathway via induction of PP2A C subunit
RT cytoplasm translocation and inhibition of c-Jun dephosphorylation at
RT Thr239.";
RL Mol. Immunol. 88:79-88(2017).
RN [28]
RP FUNCTION, AND INTERACTION WITH AMBRA1.
RX PubMed=30513302; DOI=10.1016/j.devcel.2018.11.010;
RA Becher J., Simula L., Volpe E., Procaccini C., La Rocca C., D'Acunzo P.,
RA Cianfanelli V., Strappazzon F., Caruana I., Nazio F., Weber G.,
RA Gigantino V., Botti G., Ciccosanti F., Borsellino G., Campello S.,
RA Mandolesi G., De Bardi M., Fimia G.M., D'Amelio M., Ruffini F., Furlan R.,
RA Centonze D., Martino G., Braghetta P., Chrisam M., Bonaldo P., Matarese G.,
RA Locatelli F., Battistini L., Cecconi F.;
RT "AMBRA1 controls regulatory T-cell differentiation and homeostasis upstream
RT of the FOXO3-FOXP3 axis.";
RL Dev. Cell 47:592-607(2018).
RN [29]
RP CATALYTIC ACTIVITY, AND INTERACTION WITH CRTC3.
RX PubMed=30611118; DOI=10.1016/j.isci.2018.12.012;
RA Sonntag T., Ostojic J., Vaughan J.M., Moresco J.J., Yoon Y.S.,
RA Yates J.R. III, Montminy M.;
RT "Mitogenic Signals Stimulate the CREB Coactivator CRTC3 through PP2A
RT Recruitment.";
RL IScience 11:134-145(2018).
RN [30]
RP INTERACTION WITH TRAF3IP3.
RX PubMed=30115741; DOI=10.1084/jem.20180397;
RA Yu X., Teng X.L., Wang F., Zheng Y., Qu G., Zhou Y., Hu Z., Wu Z.,
RA Chang Y., Chen L., Li H.B., Su B., Lu L., Liu Z., Sun S.C., Zou Q.;
RT "Metabolic control of regulatory T cell stability and function by TRAF3IP3
RT at the lysosome.";
RL J. Exp. Med. 215:2463-2476(2018).
RN [31]
RP FUNCTION.
RX PubMed=33108758; DOI=10.1016/j.molcel.2020.10.008;
RA Li F., Kozono D., Deraska P., Branigan T., Dunn C., Zheng X.F., Parmar K.,
RA Nguyen H., DeCaprio J., Shapiro G.I., Chowdhury D., D'Andrea A.D.;
RT "CHK1 Inhibitor Blocks Phosphorylation of FAM122A and Promotes Replication
RT Stress.";
RL Mol. Cell 0:0-0(2020).
RN [32]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) IN COMPLEX WITH MANGANESE IONS, AND
RP COFACTOR.
RX PubMed=17055435; DOI=10.1016/j.cell.2006.09.025;
RA Xing Y., Xu Y., Chen Y., Jeffrey P.D., Chao Y., Lin Z., Li Z., Strack S.,
RA Stock J.B., Shi Y.;
RT "Structure of protein phosphatase 2A core enzyme bound to tumor-inducing
RT toxins.";
RL Cell 127:341-353(2006).
RN [33]
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) IN COMPLEX WITH PPP2R1A AND PPME1.
RX PubMed=18394995; DOI=10.1016/j.cell.2008.02.041;
RA Xing Y., Li Z., Chen Y., Stock J.B., Jeffrey P.D., Shi Y.;
RT "Structural mechanism of demethylation and inactivation of protein
RT phosphatase 2A.";
RL Cell 133:154-163(2008).
RN [34]
RP INVOLVEMENT IN NEDLBA, VARIANTS NEDLBA VAL-60; GLY-88; HIS-122;
RP 125-GLN--LEU-309 DEL; CYS-127; HIS-131; ARG-191; 214-ARG--LEU-309 DEL;
RP HIS-223; VAL-223; CYS-265; 295-ARG--LEU-309 DEL AND PHE-308 INS,
RP CHARACTERIZATION OF VARIANTS NEDLBA GLY-88; HIS-122; 125-GLN--LEU-309 DEL;
RP CYS-127; HIS-131; ARG-191; 214-ARG--LEU-309 DEL; HIS-223; VAL-223; CYS-265;
RP 295-ARG--LEU-309 DEL AND PHE-308 INS, CATALYTIC ACTIVITY, MUTAGENESIS OF
RP ASP-85, CARBOXYMETHYLATION, AND INTERACTION WITH PP2A SUBUNIT A AND PP2A
RP SUBUNITS B.
RX PubMed=30595372; DOI=10.1016/j.ajhg.2018.12.002;
RA Reynhout S., Jansen S., Haesen D., van Belle S., de Munnik S.A.,
RA Bongers E.M.H.F., Schieving J.H., Marcelis C., Amiel J., Rio M.,
RA Mclaughlin H., Ladda R., Sell S., Kriek M., Peeters-Scholte C.M.P.C.D.,
RA Terhal P.A., van Gassen K.L., Verbeek N., Henry S., Scott Schwoerer J.,
RA Malik S., Revencu N., Ferreira C.R., Macnamara E., Braakman H.M.H.,
RA Brimble E., Ruzhnikov M.R.Z., Wagner M., Harrer P., Wieczorek D.,
RA Kuechler A., Tziperman B., Barel O., de Vries B.B.A., Gordon C.T.,
RA Janssens V., Vissers L.E.L.M.;
RT "De novo mutations affecting the catalytic C alpha subunit of PP2A, PPP2CA,
RT cause syndromic intellectual disability resembling other PP2A-related
RT neurodevelopmental disorders.";
RL Am. J. Hum. Genet. 104:139-156(2019).
CC -!- FUNCTION: PP2A is the major phosphatase for microtubule-associated
CC proteins (MAPs) (PubMed:22613722). PP2A can modulate the activity of
CC phosphorylase B kinase casein kinase 2, mitogen-stimulated S6 kinase,
CC and MAP-2 kinase (PubMed:22613722). Cooperates with SGO2 to protect
CC centromeric cohesin from separase-mediated cleavage in oocytes
CC specifically during meiosis I (By similarity). Can dephosphorylate SV40
CC large T antigen and p53/TP53 (PubMed:17245430). Activates RAF1 by
CC dephosphorylating it at 'Ser-259' (PubMed:10801873). Mediates
CC dephosphorylation of WEE1, preventing its ubiquitin-mediated
CC proteolysis, increasing WEE1 protein levels, and promoting the G2/M
CC checkpoint (PubMed:33108758). Mediates dephosphorylation of MYC;
CC promoting its ubiquitin-mediated proteolysis: interaction with AMBRA1
CC enhances interaction between PPP2CA and MYC (PubMed:25438055). Mediates
CC dephosphorylation of FOXO3; promoting its stabilization: interaction
CC with AMBRA1 enhances interaction between PPP2CA and FOXO3
CC (PubMed:30513302). {ECO:0000250|UniProtKB:P63330,
CC ECO:0000269|PubMed:10801873, ECO:0000269|PubMed:17245430,
CC ECO:0000269|PubMed:22613722, ECO:0000269|PubMed:25438055,
CC ECO:0000269|PubMed:30513302, ECO:0000269|PubMed:33108758,
CC ECO:0000269|PubMed:9920888}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + O-phospho-L-seryl-[protein] = L-seryl-[protein] +
CC phosphate; Xref=Rhea:RHEA:20629, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15377, ChEBI:CHEBI:29999, ChEBI:CHEBI:43474,
CC ChEBI:CHEBI:83421; EC=3.1.3.16;
CC Evidence={ECO:0000269|PubMed:1848668};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + O-phospho-L-threonyl-[protein] = L-threonyl-[protein] +
CC phosphate; Xref=Rhea:RHEA:47004, Rhea:RHEA-COMP:11060, Rhea:RHEA-
CC COMP:11605, ChEBI:CHEBI:15377, ChEBI:CHEBI:30013, ChEBI:CHEBI:43474,
CC ChEBI:CHEBI:61977; EC=3.1.3.16;
CC Evidence={ECO:0000269|PubMed:30595372, ECO:0000269|PubMed:30611118};
CC -!- COFACTOR:
CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
CC Evidence={ECO:0000269|PubMed:17055435};
CC Note=Binds 2 manganese ions per subunit. {ECO:0000269|PubMed:17055435};
CC -!- SUBUNIT: PP2A consists of a common heterodimeric core enzyme, composed
CC of PPP2CA a 36 kDa catalytic subunit (subunit C) and PPP2R1A a 65 kDa
CC constant regulatory subunit (PR65 or subunit A), that associates with a
CC variety of regulatory subunits (PubMed:17055435, PubMed:18394995,
CC PubMed:30595372). Proteins that associate with the core dimer include
CC three families of regulatory subunits B (the R2/B/PR55/B55,
CC R3/B''/PR72/PR130/PR59 and R5/B'/B56 families), the 48 kDa variable
CC regulatory subunit, viral proteins, and cell signaling molecules
CC (PubMed:18394995, PubMed:30595372). Interacts with NXN; the interaction
CC is direct (By similarity). Interacts with KCTD20 (By similarity).
CC Interacts with BTBD10 (By similarity). Interacts with SGO1 and SGO2
CC (PubMed:16580887, PubMed:16541025, PubMed:17485487). Interacts with
CC TP53 (PubMed:17245430). Interacts with AXIN1; the interaction
CC dephosphorylates AXIN1 (PubMed:9920888). Interacts with PIM3; this
CC interaction promotes dephosphorylation, ubiquitination and proteasomal
CC degradation of PIM3 (PubMed:12473674). Interacts with RAF1
CC (PubMed:10801873). Interaction with IGBP1 protects unassembled PPP2CA
CC from degradative ubiquitination (PubMed:9647778, PubMed:19818709,
CC PubMed:20092282). Interacts with GSK3B (via C2 domain)
CC (PubMed:20080667). Interacts with MFHAS1; retains PPP2CA into the
CC cytoplasm and excludes it from the nucleus (PubMed:28609714). Interacts
CC with PABIR1/FAM122A (PubMed:27588481). Interacts with ADCY8;
CC interaction is phosphatase activity-dependent; antagonizes interaction
CC between ADCY8 and calmodulin (PubMed:16258073). Interacts with CRTC3
CC (when phosphorylated at 'Ser-391') (PubMed:30611118). Interacts with
CC SPRY2; the interaction is inhibited by TESK1 interaction with SPRY2,
CC possibly by vesicular sequestration of SPRY2 (PubMed:17974561).
CC Interacts with TRAF3IP3 (PubMed:30115741). Interacts with AMBRA1 (via
CC PxP motifs); enhancing interaction between PPP2CA and MYC or FOXO3
CC (PubMed:25438055, PubMed:30513302). Forms a complex with AMBRA1 and
CC BECN1; AMBRA1 and BECN1 components of the complex regulate MYC
CC stability via different pathways (PubMed:25803737).
CC {ECO:0000250|UniProtKB:P63330, ECO:0000269|PubMed:10801873,
CC ECO:0000269|PubMed:12473674, ECO:0000269|PubMed:16258073,
CC ECO:0000269|PubMed:16541025, ECO:0000269|PubMed:16580887,
CC ECO:0000269|PubMed:17055435, ECO:0000269|PubMed:17245430,
CC ECO:0000269|PubMed:17485487, ECO:0000269|PubMed:17974561,
CC ECO:0000269|PubMed:18394995, ECO:0000269|PubMed:19818709,
CC ECO:0000269|PubMed:20080667, ECO:0000269|PubMed:20092282,
CC ECO:0000269|PubMed:25438055, ECO:0000269|PubMed:25803737,
CC ECO:0000269|PubMed:27588481, ECO:0000269|PubMed:28609714,
CC ECO:0000269|PubMed:30115741, ECO:0000269|PubMed:30513302,
CC ECO:0000269|PubMed:30595372, ECO:0000269|PubMed:30611118,
CC ECO:0000269|PubMed:9647778, ECO:0000269|PubMed:9920888}.
CC -!- INTERACTION:
CC P67775; P31749: AKT1; NbExp=4; IntAct=EBI-712311, EBI-296087;
CC P67775; P39687: ANP32A; NbExp=2; IntAct=EBI-712311, EBI-359234;
CC P67775; P05067: APP; NbExp=3; IntAct=EBI-712311, EBI-77613;
CC P67775; Q3SXR2: C3orf36; NbExp=3; IntAct=EBI-712311, EBI-18036948;
CC P67775; Q16740: CLPP; NbExp=3; IntAct=EBI-712311, EBI-1056029;
CC P67775; P06730: EIF4E; NbExp=2; IntAct=EBI-712311, EBI-73440;
CC P67775; P46695: IER3; NbExp=2; IntAct=EBI-712311, EBI-1748945;
CC P67775; P78318: IGBP1; NbExp=18; IntAct=EBI-712311, EBI-1055954;
CC P67775; O14920: IKBKB; NbExp=3; IntAct=EBI-712311, EBI-81266;
CC P67775; Q9Y6K9: IKBKG; NbExp=4; IntAct=EBI-712311, EBI-81279;
CC P67775; Q14653: IRF3; NbExp=4; IntAct=EBI-712311, EBI-2650369;
CC P67775; Q969F8: KISS1R; NbExp=3; IntAct=EBI-712311, EBI-8481408;
CC P67775; Q96JM7-2: L3MBTL3; NbExp=3; IntAct=EBI-712311, EBI-11985629;
CC P67775; P30153: PPP2R1A; NbExp=46; IntAct=EBI-712311, EBI-302388;
CC P67775; P30154: PPP2R1B; NbExp=8; IntAct=EBI-712311, EBI-357094;
CC P67775; Q9Y2T4: PPP2R2C; NbExp=3; IntAct=EBI-712311, EBI-1774058;
CC P67775; Q15172: PPP2R5A; NbExp=6; IntAct=EBI-712311, EBI-641666;
CC P67775; Q15173: PPP2R5B; NbExp=6; IntAct=EBI-712311, EBI-1369497;
CC P67775; Q13362: PPP2R5C; NbExp=10; IntAct=EBI-712311, EBI-1266156;
CC P67775; P04049: RAF1; NbExp=2; IntAct=EBI-712311, EBI-365996;
CC P67775; P28749: RBL1; NbExp=2; IntAct=EBI-712311, EBI-971402;
CC P67775; Q08999: RBL2; NbExp=2; IntAct=EBI-712311, EBI-971439;
CC P67775; Q04206: RELA; NbExp=6; IntAct=EBI-712311, EBI-73886;
CC P67775; Q5FBB7: SGO1; NbExp=4; IntAct=EBI-712311, EBI-989069;
CC P67775; Q5VSL9: STRIP1; NbExp=7; IntAct=EBI-712311, EBI-1773588;
CC P67775; O43815: STRN; NbExp=5; IntAct=EBI-712311, EBI-1046642;
CC P67775; O75663: TIPRL; NbExp=3; IntAct=EBI-712311, EBI-1054735;
CC P67775; Q9UPQ4-2: TRIM35; NbExp=3; IntAct=EBI-712311, EBI-17716262;
CC P67775; Q15645: TRIP13; NbExp=6; IntAct=EBI-712311, EBI-358993;
CC P67775; Q5T6F2: UBAP2; NbExp=3; IntAct=EBI-712311, EBI-2514383;
CC P67775; Q08AM6: VAC14; NbExp=3; IntAct=EBI-712311, EBI-2107455;
CC P67775; P03129: E7; Xeno; NbExp=3; IntAct=EBI-712311, EBI-866453;
CC P67775; P04020: E7; Xeno; NbExp=2; IntAct=EBI-712311, EBI-7005254;
CC P67775; Q61249: Igbp1; Xeno; NbExp=3; IntAct=EBI-712311, EBI-7002233;
CC P67775; P97346: Nxn; Xeno; NbExp=2; IntAct=EBI-712311, EBI-309684;
CC P67775-1; Q9Y570: PPME1; NbExp=2; IntAct=EBI-16765970, EBI-1772895;
CC P67775-1; P30153: PPP2R1A; NbExp=5; IntAct=EBI-16765970, EBI-302388;
CC P67775-1; O75663: TIPRL; NbExp=3; IntAct=EBI-16765970, EBI-1054735;
CC P67775-2; O75663: TIPRL; NbExp=3; IntAct=EBI-16766021, EBI-1054735;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:16541025}. Nucleus
CC {ECO:0000269|PubMed:16541025}. Chromosome, centromere
CC {ECO:0000269|PubMed:16541025}. Cytoplasm, cytoskeleton, spindle pole
CC {ECO:0000269|PubMed:16541025}. Note=In prometaphase cells, but not in
CC anaphase cells, localizes at centromeres (PubMed:16541025). During
CC mitosis, also found at spindle poles (PubMed:16541025). Centromeric
CC localization requires the presence of SGO2 (By similarity).
CC {ECO:0000250|UniProtKB:P63330, ECO:0000269|PubMed:16541025}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=PP2Acalpha1;
CC IsoId=P67775-1; Sequence=Displayed;
CC Name=2; Synonyms=PP2Acalpha2;
CC IsoId=P67775-2; Sequence=VSP_044320;
CC -!- PTM: Reversibly methyl esterified on Leu-309 by leucine carboxyl
CC methyltransferase 1 (LCMT1) and protein phosphatase methylesterase 1
CC (PPME1). Carboxyl methylation influences the affinity of the catalytic
CC subunit for the different regulatory subunits, thereby modulating the
CC PP2A holoenzyme's substrate specificity, enzyme activity and cellular
CC localization. {ECO:0000269|PubMed:8206937}.
CC -!- PTM: Phosphorylation of either threonine (by autophosphorylation-
CC activated protein kinase) or tyrosine results in inactivation of the
CC phosphatase. Auto-dephosphorylation has been suggested as a mechanism
CC for reactivation. {ECO:0000250|UniProtKB:P67774}.
CC -!- PTM: Polyubiquitinated, leading to its degradation by the proteasome.
CC {ECO:0000269|PubMed:27588481}.
CC -!- DISEASE: Neurodevelopmental disorder and language delay with or without
CC structural brain abnormalities (NEDLBA) [MIM:618354]: An autosomal
CC dominant neurodevelopmental disorder characterized by global
CC developmental delay with onset in infancy and additional variable
CC features including hypotonia, epilepsy, brain abnormalities such as
CC ventriculomegaly and a small corpus callosum, and autism spectrum
CC disorder. {ECO:0000269|PubMed:30595372}. Note=The disease is caused by
CC variants affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: [Isoform 2]: Catalytically inactive, shows enhanced
CC binding to IGBP1, and does not interact with the scaffolding subunit
CC PPP2R1A. {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the PPP phosphatase family. PP-1 subfamily.
CC {ECO:0000305}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; X12646; CAA31176.1; -; mRNA.
DR EMBL; J03804; AAB38019.1; -; mRNA.
DR EMBL; M60483; AAA36466.1; -; Genomic_DNA.
DR EMBL; BC000400; AAH00400.1; -; mRNA.
DR EMBL; BC002657; AAH02657.1; -; mRNA.
DR EMBL; BC019275; AAH19275.1; -; mRNA.
DR EMBL; BC031696; AAH31696.1; -; mRNA.
DR CCDS; CCDS4173.1; -. [P67775-1]
DR PIR; S01986; PAHU2A.
DR RefSeq; NP_002706.1; NM_002715.2. [P67775-1]
DR PDB; 2IAE; X-ray; 3.50 A; C/F=1-309.
DR PDB; 2IE3; X-ray; 2.80 A; C=1-309.
DR PDB; 2IE4; X-ray; 2.60 A; C=1-309.
DR PDB; 2NPP; X-ray; 3.30 A; C/F=1-309.
DR PDB; 2NYL; X-ray; 3.80 A; C/F=2-294.
DR PDB; 2NYM; X-ray; 3.60 A; C/F=2-294.
DR PDB; 3C5W; X-ray; 2.80 A; C=1-309.
DR PDB; 3DW8; X-ray; 2.85 A; C/F=1-309.
DR PDB; 3FGA; X-ray; 2.70 A; C=1-309.
DR PDB; 3K7V; X-ray; 2.85 A; C=1-309.
DR PDB; 3K7W; X-ray; 2.96 A; C=1-309.
DR PDB; 3P71; X-ray; 2.70 A; C=1-309.
DR PDB; 4I5L; X-ray; 2.43 A; C/F=1-309.
DR PDB; 4I5N; X-ray; 2.80 A; C/F=1-309.
DR PDB; 4IYP; X-ray; 2.80 A; C=6-153.
DR PDB; 4LAC; X-ray; 2.82 A; C=1-309.
DR PDB; 4NY3; X-ray; 1.80 A; C/D=304-309.
DR PDB; 5W0W; X-ray; 3.80 A; C/F/I/L=1-309.
DR PDB; 6NTS; EM; 3.63 A; C=1-301.
DR PDB; 7CUN; EM; 3.50 A; Q=1-309.
DR PDB; 7K36; EM; 3.30 A; C=1-309.
DR PDB; 7PKS; EM; 3.60 A; q=1-309.
DR PDBsum; 2IAE; -.
DR PDBsum; 2IE3; -.
DR PDBsum; 2IE4; -.
DR PDBsum; 2NPP; -.
DR PDBsum; 2NYL; -.
DR PDBsum; 2NYM; -.
DR PDBsum; 3C5W; -.
DR PDBsum; 3DW8; -.
DR PDBsum; 3FGA; -.
DR PDBsum; 3K7V; -.
DR PDBsum; 3K7W; -.
DR PDBsum; 3P71; -.
DR PDBsum; 4I5L; -.
DR PDBsum; 4I5N; -.
DR PDBsum; 4IYP; -.
DR PDBsum; 4LAC; -.
DR PDBsum; 4NY3; -.
DR PDBsum; 5W0W; -.
DR PDBsum; 6NTS; -.
DR PDBsum; 7CUN; -.
DR PDBsum; 7K36; -.
DR PDBsum; 7PKS; -.
DR AlphaFoldDB; P67775; -.
DR SMR; P67775; -.
DR BioGRID; 111507; 421.
DR CORUM; P67775; -.
DR DIP; DIP-29395N; -.
DR IntAct; P67775; 223.
DR MINT; P67775; -.
DR STRING; 9606.ENSP00000418447; -.
DR BindingDB; P67775; -.
DR ChEMBL; CHEMBL4703; -.
DR DrugBank; DB06905; (2S,3S,4E,6E,8S,9S)-3-amino-9-methoxy-2,6,8-trimethyl-10-phenyldeca-4,6-dienoic acid.
DR DrugBank; DB02506; 2,6,8-Trimethyl-3-Amino-9-Benzyl-9-Methoxynonanoic Acid.
DR DrugBank; DB00163; Vitamin E.
DR DEPOD; PPP2CA; -.
DR GlyGen; P67775; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; P67775; -.
DR PhosphoSitePlus; P67775; -.
DR SwissPalm; P67775; -.
DR BioMuta; PPP2CA; -.
DR DMDM; 54038809; -.
DR EPD; P67775; -.
DR jPOST; P67775; -.
DR MassIVE; P67775; -.
DR MaxQB; P67775; -.
DR PaxDb; P67775; -.
DR PeptideAtlas; P67775; -.
DR PRIDE; P67775; -.
DR ProteomicsDB; 57521; -. [P67775-1]
DR Antibodypedia; 3550; 674 antibodies from 45 providers.
DR DNASU; 5515; -.
DR Ensembl; ENST00000481195.6; ENSP00000418447.1; ENSG00000113575.10. [P67775-1]
DR GeneID; 5515; -.
DR KEGG; hsa:5515; -.
DR MANE-Select; ENST00000481195.6; ENSP00000418447.1; NM_002715.4; NP_002706.1.
DR UCSC; uc003kze.4; human. [P67775-1]
DR CTD; 5515; -.
DR DisGeNET; 5515; -.
DR GeneCards; PPP2CA; -.
DR HGNC; HGNC:9299; PPP2CA.
DR HPA; ENSG00000113575; Low tissue specificity.
DR MalaCards; PPP2CA; -.
DR MIM; 176915; gene.
DR MIM; 618354; phenotype.
DR neXtProt; NX_P67775; -.
DR OpenTargets; ENSG00000113575; -.
DR PharmGKB; PA33663; -.
DR VEuPathDB; HostDB:ENSG00000113575; -.
DR eggNOG; KOG0371; Eukaryota.
DR GeneTree; ENSGT00550000074618; -.
DR HOGENOM; CLU_004962_0_5_1; -.
DR InParanoid; P67775; -.
DR OMA; SWSHQES; -.
DR PhylomeDB; P67775; -.
DR TreeFam; TF105559; -.
DR BioCyc; MetaCyc:HS03696-MON; -.
DR BRENDA; 3.1.3.16; 2681.
DR PathwayCommons; P67775; -.
DR Reactome; R-HSA-113501; Inhibition of replication initiation of damaged DNA by RB1/E2F1.
DR Reactome; R-HSA-1295596; Spry regulation of FGF signaling.
DR Reactome; R-HSA-141444; Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal.
DR Reactome; R-HSA-163685; Integration of energy metabolism.
DR Reactome; R-HSA-163767; PP2A-mediated dephosphorylation of key metabolic factors.
DR Reactome; R-HSA-180024; DARPP-32 events.
DR Reactome; R-HSA-195253; Degradation of beta-catenin by the destruction complex.
DR Reactome; R-HSA-196299; Beta-catenin phosphorylation cascade.
DR Reactome; R-HSA-198753; ERK/MAPK targets.
DR Reactome; R-HSA-202670; ERKs are inactivated.
DR Reactome; R-HSA-2465910; MASTL Facilitates Mitotic Progression.
DR Reactome; R-HSA-2467813; Separation of Sister Chromatids.
DR Reactome; R-HSA-2500257; Resolution of Sister Chromatid Cohesion.
DR Reactome; R-HSA-2995383; Initiation of Nuclear Envelope (NE) Reformation.
DR Reactome; R-HSA-389513; CTLA4 inhibitory signaling.
DR Reactome; R-HSA-432142; Platelet sensitization by LDL.
DR Reactome; R-HSA-4641262; Disassembly of the destruction complex and recruitment of AXIN to the membrane.
DR Reactome; R-HSA-5339716; Signaling by GSK3beta mutants.
DR Reactome; R-HSA-5358747; CTNNB1 S33 mutants aren't phosphorylated.
DR Reactome; R-HSA-5358749; CTNNB1 S37 mutants aren't phosphorylated.
DR Reactome; R-HSA-5358751; CTNNB1 S45 mutants aren't phosphorylated.
DR Reactome; R-HSA-5358752; CTNNB1 T41 mutants aren't phosphorylated.
DR Reactome; R-HSA-5467337; APC truncation mutants have impaired AXIN binding.
DR Reactome; R-HSA-5467340; AXIN missense mutants destabilize the destruction complex.
DR Reactome; R-HSA-5467348; Truncations of AMER1 destabilize the destruction complex.
DR Reactome; R-HSA-5663220; RHO GTPases Activate Formins.
DR Reactome; R-HSA-5673000; RAF activation.
DR Reactome; R-HSA-5675221; Negative regulation of MAPK pathway.
DR Reactome; R-HSA-6804757; Regulation of TP53 Degradation.
DR Reactome; R-HSA-6811558; PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling.
DR Reactome; R-HSA-68877; Mitotic Prometaphase.
DR Reactome; R-HSA-69231; Cyclin D associated events in G1.
DR Reactome; R-HSA-69273; Cyclin A/B1/B2 associated events during G2/M transition.
DR Reactome; R-HSA-9634600; Regulation of glycolysis by fructose 2,6-bisphosphate metabolism.
DR Reactome; R-HSA-9648025; EML4 and NUDC in mitotic spindle formation.
DR Reactome; R-HSA-975957; Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC).
DR SignaLink; P67775; -.
DR SIGNOR; P67775; -.
DR BioGRID-ORCS; 5515; 587 hits in 1102 CRISPR screens.
DR ChiTaRS; PPP2CA; human.
DR EvolutionaryTrace; P67775; -.
DR GeneWiki; PPP2CA; -.
DR GenomeRNAi; 5515; -.
DR Pharos; P67775; Tchem.
DR PRO; PR:P67775; -.
DR Proteomes; UP000005640; Chromosome 5.
DR RNAct; P67775; protein.
DR Bgee; ENSG00000113575; Expressed in lateral nuclear group of thalamus and 207 other tissues.
DR ExpressionAtlas; P67775; baseline and differential.
DR Genevisible; P67775; HS.
DR GO; GO:0000775; C:chromosome, centromeric region; IEA:UniProtKB-SubCell.
DR GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0016020; C:membrane; NAS:UniProtKB.
DR GO; GO:0045121; C:membrane raft; IDA:UniProtKB.
DR GO; GO:0015630; C:microtubule cytoskeleton; NAS:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; NAS:UniProtKB.
DR GO; GO:0005634; C:nucleus; NAS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IEA:Ensembl.
DR GO; GO:0000159; C:protein phosphatase type 2A complex; IDA:UniProtKB.
DR GO; GO:0000922; C:spindle pole; IEA:UniProtKB-SubCell.
DR GO; GO:0045202; C:synapse; IEA:Ensembl.
DR GO; GO:0050811; F:GABA receptor binding; IEA:Ensembl.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0017018; F:myosin phosphatase activity; IEA:UniProtKB-EC.
DR GO; GO:0004721; F:phosphoprotein phosphatase activity; TAS:ARUK-UCL.
DR GO; GO:0008022; F:protein C-terminus binding; IEA:Ensembl.
DR GO; GO:0046982; F:protein heterodimerization activity; IPI:UniProtKB.
DR GO; GO:0004722; F:protein serine/threonine phosphatase activity; IDA:UniProtKB.
DR GO; GO:0004725; F:protein tyrosine phosphatase activity; IDA:UniProtKB.
DR GO; GO:0048156; F:tau protein binding; NAS:ARUK-UCL.
DR GO; GO:0006915; P:apoptotic process; TAS:UniProtKB.
DR GO; GO:0006672; P:ceramide metabolic process; NAS:UniProtKB.
DR GO; GO:0051321; P:meiotic cell cycle; IEA:UniProtKB-KW.
DR GO; GO:0007498; P:mesoderm development; IEA:Ensembl.
DR GO; GO:0000278; P:mitotic cell cycle; IBA:GO_Central.
DR GO; GO:0030308; P:negative regulation of cell growth; NAS:UniProtKB.
DR GO; GO:0010719; P:negative regulation of epithelial to mesenchymal transition; IMP:BHF-UCL.
DR GO; GO:0051898; P:negative regulation of protein kinase B signaling; IMP:ARUK-UCL.
DR GO; GO:0042532; P:negative regulation of tyrosine phosphorylation of STAT protein; NAS:UniProtKB.
DR GO; GO:0070262; P:peptidyl-serine dephosphorylation; TAS:ARUK-UCL.
DR GO; GO:0035970; P:peptidyl-threonine dephosphorylation; IDA:UniProtKB.
DR GO; GO:1904528; P:positive regulation of microtubule binding; ISS:ARUK-UCL.
DR GO; GO:0071902; P:positive regulation of protein serine/threonine kinase activity; IMP:BHF-UCL.
DR GO; GO:0006470; P:protein dephosphorylation; IMP:UniProtKB.
DR GO; GO:0030155; P:regulation of cell adhesion; NAS:UniProtKB.
DR GO; GO:0045595; P:regulation of cell differentiation; NAS:UniProtKB.
DR GO; GO:0006275; P:regulation of DNA replication; NAS:UniProtKB.
DR GO; GO:2000045; P:regulation of G1/S transition of mitotic cell cycle; IDA:UniProtKB.
DR GO; GO:0040008; P:regulation of growth; NAS:UniProtKB.
DR GO; GO:1904526; P:regulation of microtubule binding; NAS:ARUK-UCL.
DR GO; GO:0001932; P:regulation of protein phosphorylation; NAS:ARUK-UCL.
DR GO; GO:0006355; P:regulation of transcription, DNA-templated; NAS:UniProtKB.
DR GO; GO:0030111; P:regulation of Wnt signaling pathway; NAS:UniProtKB.
DR GO; GO:0010288; P:response to lead ion; ISS:ARUK-UCL.
DR GO; GO:0010033; P:response to organic substance; NAS:UniProtKB.
DR GO; GO:0008380; P:RNA splicing; NAS:UniProtKB.
DR GO; GO:0019932; P:second-messenger-mediated signaling; NAS:UniProtKB.
DR Gene3D; 3.60.21.10; -; 1.
DR InterPro; IPR004843; Calcineurin-like_PHP_ApaH.
DR InterPro; IPR029052; Metallo-depent_PP-like.
DR InterPro; IPR006186; Ser/Thr-sp_prot-phosphatase.
DR Pfam; PF00149; Metallophos; 1.
DR PRINTS; PR00114; STPHPHTASE.
DR SMART; SM00156; PP2Ac; 1.
DR SUPFAM; SSF56300; SSF56300; 1.
DR PROSITE; PS00125; SER_THR_PHOSPHATASE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Centromere; Chromosome; Cytoplasm;
KW Cytoskeleton; Direct protein sequencing; Disease variant; Hydrolase;
KW Intellectual disability; Manganese; Meiosis; Metal-binding; Methylation;
KW Nucleus; Phosphoprotein; Protein phosphatase; Reference proteome;
KW Ubl conjugation.
FT CHAIN 1..309
FT /note="Serine/threonine-protein phosphatase 2A catalytic
FT subunit alpha isoform"
FT /id="PRO_0000058839"
FT ACT_SITE 118
FT /note="Proton donor"
FT /evidence="ECO:0000250|UniProtKB:P36873"
FT BINDING 57
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:17055435"
FT BINDING 59
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:17055435"
FT BINDING 85
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:17055435"
FT BINDING 85
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:17055435"
FT BINDING 117
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:17055435"
FT BINDING 167
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:17055435"
FT BINDING 241
FT /ligand="Mn(2+)"
FT /ligand_id="ChEBI:CHEBI:29035"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:17055435"
FT MOD_RES 307
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:P67774"
FT MOD_RES 309
FT /note="Leucine methyl ester"
FT /evidence="ECO:0000269|PubMed:8206937"
FT VAR_SEQ 193..246
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000305"
FT /id="VSP_044320"
FT VARIANT 52
FT /note="V -> A (in dbSNP:rs11552681)"
FT /id="VAR_051735"
FT VARIANT 60
FT /note="G -> V (in NEDLBA; unknown pathological
FT significance; dbSNP:rs1580641099)"
FT /evidence="ECO:0000269|PubMed:30595372"
FT /id="VAR_082064"
FT VARIANT 88
FT /note="D -> G (in NEDLBA; loss of phosphatase activity in
FT an in vitro assay; strong decrease in C-terminal
FT methylation; decreased interaction with PP2A subunit A
FT PPP2R1A/PPP2R1B; loss of interaction with PP2A subunit B
FT component PPP2R2A; decreased interaction with PP2A subunit
FT B components PPP2R5A, PPP2R5B, PPP2R5E, PPP2R3A and STRN3;
FT dbSNP:rs1561737008)"
FT /evidence="ECO:0000269|PubMed:30595372"
FT /id="VAR_082065"
FT VARIANT 122
FT /note="Q -> H (in NEDLBA; decreased phosphatase activity in
FT an in vitro assay; no effect on the interaction with PP2A
FT subunit A PPP2R1A/PPP2R1B; increased interaction with PP2A
FT subunit B component STRN3; no effect on interaction with
FT other PP2A subunit B components; dbSNP:rs764595667)"
FT /evidence="ECO:0000269|PubMed:30595372"
FT /id="VAR_082066"
FT VARIANT 125..309
FT /note="Missing (in NEDLBA; may be expressed at very low
FT levels, if any)"
FT /evidence="ECO:0000269|PubMed:30595372"
FT /id="VAR_082067"
FT VARIANT 127
FT /note="Y -> C (in NEDLBA; almost complete loss of
FT phosphatase activity in an in vitro assay; strong decrease
FT in C-terminal methylation; no effect on the interaction
FT with PP2A subunit A PPP2R1A/PPP2R1B; decreased interaction
FT with PP2A subunit B components PPP2R5A, PPP2R5B, PPP2R5C,
FT PPP2R5D, PPP2R5E and PPP2R3A; no effect on interaction with
FT PP2A subunit B component PPP2R2A; dbSNP:rs1580637688)"
FT /evidence="ECO:0000269|PubMed:30595372"
FT /id="VAR_082068"
FT VARIANT 131
FT /note="D -> H (in NEDLBA; increased phosphatase activity in
FT an in vitro assay; no effect on C-terminal methylation;
FT decreased interaction with PP2A subunit A PPP2R1A/PPP2R1B;
FT loss of interaction with PP2A subunit B components PPP2R5A,
FT PPP2R5B, PPP2R5C, PPP2R5D and PPP2R5E; no effect on
FT interaction with PP2A subunit B components PPP2R2A and
FT PPP2R3A; dbSNP:rs1580637673)"
FT /evidence="ECO:0000269|PubMed:30595372"
FT /id="VAR_082069"
FT VARIANT 191
FT /note="H -> R (in NEDLBA; decreased phosphatase activity in
FT an in vitro assay; no effect on the interaction with PP2A
FT subunit A PPP2R1A/PPP2R1B; decreased interaction with PP2A
FT subunit B component PPP2R5D; increased interaction with
FT PP2A subunit B component STRN3; no effect on interaction
FT with other PP2A subunit B components; dbSNP:rs915349596)"
FT /evidence="ECO:0000269|PubMed:30595372"
FT /id="VAR_082070"
FT VARIANT 214..309
FT /note="Missing (in NEDLBA; loss of phosphatase activity in
FT an in vitro assay; complete loss of interaction with PP2A
FT subunit A PPP2R1A/PPP2R1B; interacts with alpha4/IGBP1;
FT loss of interaction with PP2A subunit B components;
FT dbSNP:rs148071386)"
FT /evidence="ECO:0000269|PubMed:30595372"
FT /id="VAR_082071"
FT VARIANT 223
FT /note="D -> H (in NEDLBA; decreased phosphatase activity in
FT an in vitro assay; no effect on C-terminal methylation; no
FT effect on the interaction with PP2A subunit A PPP2R1A/
FT PPP2R1B; no effect on interaction with PP2A subunit B
FT components; dbSNP:rs1580636668)"
FT /evidence="ECO:0000269|PubMed:30595372"
FT /id="VAR_082072"
FT VARIANT 223
FT /note="D -> V (in NEDLBA; no effect on phosphatase activity
FT in an in vitro assay; no effect on the interaction with
FT PP2A subunit A PPP2R1A/PPP2R1B; no effect on interaction
FT with PP2A subunit B components; dbSNP:rs1580636665)"
FT /evidence="ECO:0000269|PubMed:30595372"
FT /id="VAR_082073"
FT VARIANT 265
FT /note="Y -> C (in NEDLBA; severe decrease in phosphatase
FT activity in an in vitro assay; strong decrease in C-
FT terminal methylation; decreased interaction with PP2A
FT subunit A PPP2R1A/PPP2R1B; loss of interaction with PP2A
FT subunit B components PPP2R2A, PPP2R5A, PPP2R5B, PPP2R5E,
FT PPP2R3A and STRN3; decreased interaction with PP2A subunit
FT B components PPP2R5C and PPP2R5D; dbSNP:rs1561733474)"
FT /evidence="ECO:0000269|PubMed:30595372"
FT /id="VAR_082074"
FT VARIANT 308
FT /note="F -> FF (in NEDLBA; almost complete loss of
FT phosphatase activity in an in vitro assay; decreased
FT interaction with PP2A subunit A PPP2R1A/PPP2R1B; strongly
FT decreased interaction with PP2A subunit B components
FT PPP2R2A and PPP2R3A; increased interaction with PP2A
FT subunit B component STRN3; no effect on interaction with
FT PP2A subunit B components PPP2R5A, PPP2R5B, PPP2R5C,
FT PPP2R5D and PPP2R5E)"
FT /evidence="ECO:0000269|PubMed:30595372"
FT /id="VAR_082075"
FT MUTAGEN 85
FT /note="D->N: Loss of phosphatase activity."
FT /evidence="ECO:0000269|PubMed:30595372"
FT MUTAGEN 309
FT /note="L->A: Loss of binding to PP2A B-alpha regulatory
FT subunit."
FT /evidence="ECO:0000269|PubMed:10191253"
FT HELIX 3..18
FT /evidence="ECO:0007829|PDB:4I5L"
FT HELIX 25..39
FT /evidence="ECO:0007829|PDB:4I5L"
FT STRAND 44..48
FT /evidence="ECO:0007829|PDB:4I5L"
FT STRAND 50..55
FT /evidence="ECO:0007829|PDB:4I5L"
FT HELIX 62..72
FT /evidence="ECO:0007829|PDB:4I5L"
FT TURN 75..77
FT /evidence="ECO:0007829|PDB:4I5L"
FT STRAND 80..82
FT /evidence="ECO:0007829|PDB:4I5L"
FT STRAND 87..91
FT /evidence="ECO:0007829|PDB:4I5L"
FT HELIX 93..106
FT /evidence="ECO:0007829|PDB:4I5L"
FT TURN 108..110
FT /evidence="ECO:0007829|PDB:4I5L"
FT STRAND 111..113
FT /evidence="ECO:0007829|PDB:4I5L"
FT HELIX 117..119
FT /evidence="ECO:0007829|PDB:7K36"
FT HELIX 121..127
FT /evidence="ECO:0007829|PDB:4I5L"
FT HELIX 129..137
FT /evidence="ECO:0007829|PDB:4I5L"
FT STRAND 138..140
FT /evidence="ECO:0007829|PDB:4I5L"
FT HELIX 141..150
FT /evidence="ECO:0007829|PDB:4I5L"
FT STRAND 155..159
FT /evidence="ECO:0007829|PDB:4I5L"
FT TURN 160..162
FT /evidence="ECO:0007829|PDB:4I5L"
FT STRAND 163..168
FT /evidence="ECO:0007829|PDB:4I5L"
FT HELIX 177..182
FT /evidence="ECO:0007829|PDB:4I5L"
FT STRAND 186..188
FT /evidence="ECO:0007829|PDB:3C5W"
FT STRAND 191..193
FT /evidence="ECO:0007829|PDB:4I5L"
FT HELIX 194..200
FT /evidence="ECO:0007829|PDB:4I5L"
FT STRAND 205..211
FT /evidence="ECO:0007829|PDB:4I5L"
FT STRAND 215..220
FT /evidence="ECO:0007829|PDB:4I5L"
FT HELIX 222..232
FT /evidence="ECO:0007829|PDB:4I5L"
FT STRAND 235..239
FT /evidence="ECO:0007829|PDB:4I5L"
FT STRAND 247..251
FT /evidence="ECO:0007829|PDB:4I5L"
FT TURN 252..255
FT /evidence="ECO:0007829|PDB:4I5L"
FT STRAND 256..259
FT /evidence="ECO:0007829|PDB:4I5L"
FT HELIX 265..267
FT /evidence="ECO:0007829|PDB:4I5L"
FT STRAND 273..278
FT /evidence="ECO:0007829|PDB:4I5L"
FT STRAND 284..289
FT /evidence="ECO:0007829|PDB:4I5L"
SQ SEQUENCE 309 AA; 35594 MW; C602291F78F34555 CRC64;
MDEKVFTKEL DQWIEQLNEC KQLSESQVKS LCEKAKEILT KESNVQEVRC PVTVCGDVHG
QFHDLMELFR IGGKSPDTNY LFMGDYVDRG YYSVETVTLL VALKVRYRER ITILRGNHES
RQITQVYGFY DECLRKYGNA NVWKYFTDLF DYLPLTALVD GQIFCLHGGL SPSIDTLDHI
RALDRLQEVP HEGPMCDLLW SDPDDRGGWG ISPRGAGYTF GQDISETFNH ANGLTLVSRA
HQLVMEGYNW CHDRNVVTIF SAPNYCYRCG NQAAIMELDD TLKYSFLQFD PAPRRGEPHV
TRRTPDYFL
