ID   PPE2_HUMAN              Reviewed;         753 AA.
AC   O14830; O14831;
DT   11-JAN-2001, integrated into UniProtKB/Swiss-Prot.
DT   05-MAY-2009, sequence version 2.
DT   27-MAR-2024, entry version 218.
DE   RecName: Full=Serine/threonine-protein phosphatase with EF-hands 2;
DE            Short=PPEF-2;
DE            EC=3.1.3.16;
GN   Name=PPEF2;
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] (ISOFORMS PPEF-2(S) AND PPEF-2(L)), AND VARIANT
RP   LEU-481.
RC   TISSUE=Retina;
RX   PubMed=9326663; DOI=10.1073/pnas.94.21.11639;
RA   Sherman P.M., Sun H., Macke J.P., Williams J., Smallwood P.M., Nathans J.;
RT   "Identification and characterization of a conserved family of protein
RT   serine/threonine phosphatases homologous to Drosophila retinal degeneration
RT   C.";
RL   Proc. Natl. Acad. Sci. U.S.A. 94:11639-11644(1997).
RN   [2]
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).
CC   -!- FUNCTION: May play a role in phototransduction. May dephosphorylate
CC       photoactivated rhodopsin. May function as a calcium sensing regulator
CC       of ionic currents, energy production or synaptic transmission.
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   -!- 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   -!- COFACTOR:
CC       Name=Mn(2+); Xref=ChEBI:CHEBI:29035; Evidence={ECO:0000250};
CC       Note=Binds 2 manganese ions per subunit. {ECO:0000250};
CC   -!- ACTIVITY REGULATION: Activated by calcium. {ECO:0000250}.
CC   -!- INTERACTION:
CC       O14830; P62204: Calm3; Xeno; NbExp=2; IntAct=EBI-2931306, EBI-397460;
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000305}. Cell projection, cilium,
CC       photoreceptor outer segment. Photoreceptor inner segment.
CC       Note=Localized to photoreceptors, PPEF-2(L) is at least 2 fold more
CC       abundant in rod inner segments than in the outer segments.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=PPEF-2(L);
CC         IsoId=O14830-1; Sequence=Displayed;
CC       Name=PPEF-2(S);
CC         IsoId=O14830-2; Sequence=VSP_005103, VSP_005104;
CC   -!- TISSUE SPECIFICITY: Retinal specific.
CC   -!- SIMILARITY: Belongs to the PPP phosphatase family. {ECO:0000305}.
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DR   EMBL; AF023456; AAB82796.1; -; mRNA.
DR   EMBL; AF023457; AAB82797.1; -; mRNA.
DR   EMBL; AC110615; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   CCDS; CCDS34013.1; -. [O14830-1]
DR   RefSeq; NP_006230.2; NM_006239.2. [O14830-1]
DR   RefSeq; XP_011530341.1; XM_011532039.2. [O14830-1]
DR   AlphaFoldDB; O14830; -.
DR   SMR; O14830; -.
DR   BioGRID; 111466; 28.
DR   IntAct; O14830; 23.
DR   MINT; O14830; -.
DR   STRING; 9606.ENSP00000286719; -.
DR   DEPOD; PPEF2; -.
DR   iPTMnet; O14830; -.
DR   PhosphoSitePlus; O14830; -.
DR   BioMuta; PPEF2; -.
DR   MassIVE; O14830; -.
DR   PaxDb; 9606-ENSP00000286719; -.
DR   PeptideAtlas; O14830; -.
DR   ProteomicsDB; 48266; -. [O14830-1]
DR   ProteomicsDB; 48267; -. [O14830-2]
DR   Antibodypedia; 13410; 70 antibodies from 18 providers.
DR   DNASU; 5470; -.
DR   Ensembl; ENST00000286719.12; ENSP00000286719.6; ENSG00000156194.19. [O14830-1]
DR   GeneID; 5470; -.
DR   KEGG; hsa:5470; -.
DR   MANE-Select; ENST00000286719.12; ENSP00000286719.6; NM_006239.3; NP_006230.2.
DR   UCSC; uc003hix.4; human. [O14830-1]
DR   AGR; HGNC:9244; -.
DR   CTD; 5470; -.
DR   GeneCards; PPEF2; -.
DR   HGNC; HGNC:9244; PPEF2.
DR   HPA; ENSG00000156194; Tissue enriched (retina).
DR   MIM; 602256; gene.
DR   neXtProt; NX_O14830; -.
DR   OpenTargets; ENSG00000156194; -.
DR   PharmGKB; PA33565; -.
DR   VEuPathDB; HostDB:ENSG00000156194; -.
DR   eggNOG; KOG0377; Eukaryota.
DR   GeneTree; ENSGT00940000157870; -.
DR   HOGENOM; CLU_012603_1_0_1; -.
DR   InParanoid; O14830; -.
DR   OMA; CRENKVR; -.
DR   OrthoDB; 3076469at2759; -.
DR   PhylomeDB; O14830; -.
DR   TreeFam; TF313342; -.
DR   PathwayCommons; O14830; -.
DR   SignaLink; O14830; -.
DR   BioGRID-ORCS; 5470; 9 hits in 1161 CRISPR screens.
DR   ChiTaRS; PPEF2; human.
DR   GenomeRNAi; 5470; -.
DR   Pharos; O14830; Tbio.
DR   PRO; PR:O14830; -.
DR   Proteomes; UP000005640; Chromosome 4.
DR   RNAct; O14830; Protein.
DR   Bgee; ENSG00000156194; Expressed in male germ line stem cell (sensu Vertebrata) in testis and 93 other cell types or tissues.
DR   ExpressionAtlas; O14830; baseline and differential.
DR   GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR   GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR   GO; GO:0001917; C:photoreceptor inner segment; IEA:UniProtKB-SubCell.
DR   GO; GO:0001750; C:photoreceptor outer segment; IEA:UniProtKB-SubCell.
DR   GO; GO:0005509; F:calcium ion binding; IEA:InterPro.
DR   GO; GO:0030544; F:Hsp70 protein binding; IDA:BHF-UCL.
DR   GO; GO:0051879; F:Hsp90 protein binding; IDA:BHF-UCL.
DR   GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR   GO; GO:0030145; F:manganese ion binding; IEA:InterPro.
DR   GO; GO:0031435; F:mitogen-activated protein kinase kinase kinase binding; IPI:BHF-UCL.
DR   GO; GO:0017018; F:myosin phosphatase activity; IEA:UniProtKB-EC.
DR   GO; GO:0004722; F:protein serine/threonine phosphatase activity; IBA:GO_Central.
DR   GO; GO:0050906; P:detection of stimulus involved in sensory perception; IEA:InterPro.
DR   GO; GO:0043409; P:negative regulation of MAPK cascade; IDA:BHF-UCL.
DR   GO; GO:0010801; P:negative regulation of peptidyl-threonine phosphorylation; IDA:BHF-UCL.
DR   GO; GO:0006470; P:protein dephosphorylation; TAS:ProtInc.
DR   GO; GO:0043506; P:regulation of JUN kinase activity; IC:BHF-UCL.
DR   GO; GO:0043405; P:regulation of MAP kinase activity; IC:BHF-UCL.
DR   GO; GO:0007601; P:visual perception; IEA:UniProtKB-KW.
DR   CDD; cd00051; EFh; 1.
DR   CDD; cd07420; MPP_RdgC; 1.
DR   Gene3D; 3.60.21.10; -; 2.
DR   Gene3D; 1.10.238.10; EF-hand; 1.
DR   InterPro; IPR004843; Calcineurin-like_PHP_ApaH.
DR   InterPro; IPR011992; EF-hand-dom_pair.
DR   InterPro; IPR018247; EF_Hand_1_Ca_BS.
DR   InterPro; IPR002048; EF_hand_dom.
DR   InterPro; IPR029052; Metallo-depent_PP-like.
DR   InterPro; IPR013235; PPP_dom.
DR   InterPro; IPR012008; Ser/Thr-Pase_EF-hand_contain.
DR   InterPro; IPR006186; Ser/Thr-sp_prot-phosphatase.
DR   PANTHER; PTHR45668; SERINE/THREONINE-PROTEIN PHOSPHATASE 5-RELATED; 1.
DR   PANTHER; PTHR45668:SF2; SERINE_THREONINE-PROTEIN PHOSPHATASE WITH EF-HANDS 2; 1.
DR   Pfam; PF13499; EF-hand_7; 1.
DR   Pfam; PF00149; Metallophos; 1.
DR   Pfam; PF08321; PPP5; 1.
DR   PIRSF; PIRSF000912; PPEF; 1.
DR   PRINTS; PR00114; STPHPHTASE.
DR   SMART; SM00054; EFh; 3.
DR   SMART; SM00156; PP2Ac; 1.
DR   SUPFAM; SSF47473; EF-hand; 1.
DR   SUPFAM; SSF56300; Metallo-dependent phosphatases; 1.
DR   PROSITE; PS00018; EF_HAND_1; 2.
DR   PROSITE; PS50222; EF_HAND_2; 3.
DR   PROSITE; PS00125; SER_THR_PHOSPHATASE; 1.
DR   Genevisible; O14830; HS.
PE   1: Evidence at protein level;
KW   Alternative splicing; Calcium; Cell projection; Cilium; Cytoplasm;
KW   Hydrolase; Manganese; Metal-binding; Protein phosphatase;
KW   Reference proteome; Repeat; Sensory transduction; Vision.
FT   CHAIN           1..753
FT                   /note="Serine/threonine-protein phosphatase with EF-hands
FT                   2"
FT                   /id="PRO_0000058901"
FT   DOMAIN          21..46
FT                   /note="IQ"
FT   DOMAIN          568..603
FT                   /note="EF-hand 1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT   DOMAIN          652..687
FT                   /note="EF-hand 2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT   DOMAIN          692..727
FT                   /note="EF-hand 3"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT   REGION          128..540
FT                   /note="Catalytic"
FT   REGION          318..382
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          409..435
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          732..753
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        318..336
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        356..380
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        415..435
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        738..753
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        241
FT                   /note="Proton donor"
FT                   /evidence="ECO:0000250"
FT   BINDING         179
FT                   /ligand="Mn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29035"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000250"
FT   BINDING         181
FT                   /ligand="Mn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29035"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000250"
FT   BINDING         208
FT                   /ligand="Mn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29035"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000250"
FT   BINDING         208
FT                   /ligand="Mn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29035"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000250"
FT   BINDING         240
FT                   /ligand="Mn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29035"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000250"
FT   BINDING         292
FT                   /ligand="Mn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29035"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000250"
FT   BINDING         488
FT                   /ligand="Mn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29035"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000250"
FT   BINDING         665
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT   BINDING         667
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT   BINDING         669
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT   BINDING         676
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT   BINDING         705
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT   BINDING         707
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT   BINDING         709
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT   BINDING         711
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT   BINDING         716
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT   VAR_SEQ         588..598
FT                   /note="ITLSDWAAAVE -> ASSQLCYYQQK (in isoform PPEF-2(S))"
FT                   /evidence="ECO:0000305"
FT                   /id="VSP_005103"
FT   VAR_SEQ         599..753
FT                   /note="Missing (in isoform PPEF-2(S))"
FT                   /evidence="ECO:0000305"
FT                   /id="VSP_005104"
FT   VARIANT         120
FT                   /note="S -> R"
FT                   /id="VAR_010230"
FT   VARIANT         394
FT                   /note="V -> L (in dbSNP:rs34097437)"
FT                   /id="VAR_055121"
FT   VARIANT         412
FT                   /note="E -> K (in dbSNP:rs35599561)"
FT                   /id="VAR_055122"
FT   VARIANT         481
FT                   /note="M -> L (in dbSNP:rs6858658)"
FT                   /evidence="ECO:0000269|PubMed:9326663"
FT                   /id="VAR_061759"
FT   VARIANT         553
FT                   /note="R -> K (in dbSNP:rs34155925)"
FT                   /id="VAR_055123"
FT   VARIANT         575
FT                   /note="S -> C (in dbSNP:rs17000961)"
FT                   /id="VAR_055124"
FT   CONFLICT        118
FT                   /note="R -> S (in Ref. 1; AAB82796/AAB82797)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   753 AA;  86518 MW;  28ED6E79C5B8906C CRC64;
     MGSGTSTQHH FAFQNAERAF KAAALIQRWY RRYVARLEMR RRCTWSIFQS IEYAGQQDQV
     KLHDFFSYLM DHFIPSSHND RDFLTRIFTE DRFAQDSEMK KCSDYESIEV PDSYTGPRLS
     FPLLPDHATA LVEAFRLKQQ LHARYVLNLL YETKKHLVQL PNINRVSTCY SEEITVCGDL
     HGQLDDLIFI FYKNGLPSPE RSYVFNGDFV DRGKDSVEIL MILFAFMLVY PKEFHLNRGN
     HEDHMVNLRY GFTKEVMNKY KVHGKEILRT LQDVFCWLPL ATLIDEKVLI LHGGVSDITD
     LELLDKIERS KIVSTMRCKT RQKSEKQMEE KRRANQKSSA QGPIPWFLPE SRSLPSSPLR
     LGSYKAQKTS RSSSIPCSGS LDGRELSRQV RSSVELELER CRQQAGLLVT GEKEEPSRSA
     SEADSEAGEL RKPTQEEWRQ VVDILWSDPM AQEGCKANTI RGGGCYFGPD VTQQLLQKYN
     MQFLIRSHEC KPEGYEFCHN RKVLTIFSAS NYYEVGSNRG AYVKLGPALT PHIVQYQANK
     VTHTLTMRQR ISRVEESALR ALREKLFAHS SDLLSEFKKH DADKVGLITL SDWAAAVESV
     LHLGLPWRML RPQLVNSSAD NMLEYKSWLK NLAKEQLSRE NIQSSLLETL YRNRSNLETI
     FRIIDSDHSG FISLDEFRQT WKLFSSHMNI DITDDCICDL ARSIDFNKDG HIDINEFLEA
     FRLVEKSCPE GDASECPQAT NAKDSGCSSP GAH
//