ID   FOLH1_MOUSE             Reviewed;         752 AA.
AC   O35409; Q0VDM5; Q9DCC2;
DT   11-FEB-2002, integrated into UniProtKB/Swiss-Prot.
DT   27-JUL-2011, sequence version 2.
DT   27-MAR-2024, entry version 180.
DE   RecName: Full=Glutamate carboxypeptidase 2;
DE            EC=3.4.17.21;
DE   AltName: Full=Folate hydrolase 1;
DE   AltName: Full=Folylpoly-gamma-glutamate carboxypeptidase;
DE            Short=FGCP;
DE   AltName: Full=Glutamate carboxypeptidase II;
DE            Short=GCPII;
DE   AltName: Full=Membrane glutamate carboxypeptidase;
DE            Short=mGCP;
DE   AltName: Full=N-acetylated-alpha-linked acidic dipeptidase I;
DE            Short=NAALADase I;
DE   AltName: Full=Prostate-specific membrane antigen homolog;
DE   AltName: Full=Pteroylpoly-gamma-glutamate carboxypeptidase;
GN   Name=Folh1; Synonyms=Mopsm, Naalad1;
OS   Mus musculus (Mouse).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Mus; Mus.
OX   NCBI_TaxID=10090;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   STRAIN=NIH Swiss; TISSUE=Brain;
RX   PubMed=11210180; DOI=10.1007/s003350010240;
RA   Bacich D.J., Pinto J.T., Tong W.P., Heston W.D.W.;
RT   "Cloning, expression, genomic localization, and enzymatic activities of the
RT   mouse homolog of prostate-specific membrane antigen/NAALADase/ folate
RT   hydrolase.";
RL   Mamm. Genome 12:117-123(2001).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   STRAIN=C57BL/6J; TISSUE=Kidney;
RX   PubMed=16141072; DOI=10.1126/science.1112014;
RA   Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA   Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA   Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA   Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA   Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA   Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA   Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA   Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA   Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA   Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA   Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA   Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA   Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA   Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA   Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA   Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA   Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA   Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA   Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA   Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA   Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA   Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA   Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA   Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA   Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA   van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA   Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA   Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA   Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA   Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA   Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA   Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA   Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA   Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT   "The transcriptional landscape of the mammalian genome.";
RL   Science 309:1559-1563(2005).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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   [4]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Brain, and Kidney;
RX   PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA   Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA   Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT   "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL   Cell 143:1174-1189(2010).
CC   -!- FUNCTION: Has both folate hydrolase and N-acetylated-alpha-linked-
CC       acidic dipeptidase (NAALADase) activity. Has a preference for tri-
CC       alpha-glutamate peptides (By similarity). In the intestine, required
CC       for the uptake of folate. In the brain, modulates excitatory
CC       neurotransmission through the hydrolysis of the neuropeptide, N-
CC       aceylaspartylglutamate (NAAG), thereby releasing glutamate.
CC       {ECO:0000250}.
CC   -!- FUNCTION: Also exhibits a dipeptidyl-peptidase IV type activity. In
CC       vitro, cleaves Gly-Pro-AMC. {ECO:0000250}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=Release of an unsubstituted, C-terminal glutamyl residue,
CC         typically from Ac-Asp-Glu or folylpoly-gamma-glutamates.;
CC         EC=3.4.17.21;
CC   -!- COFACTOR:
CC       Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC       Note=Binds 2 Zn(2+) ions per subunit. Required for NAALADase activity.;
CC   -!- ACTIVITY REGULATION: The NAALADase and folate hydrolase activities are
CC       inhibited by quisqualic acid.
CC   -!- SUBUNIT: Homodimer. {ECO:0000250}.
CC   -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:Q04609};
CC       Single-pass type II membrane protein {ECO:0000250|UniProtKB:Q04609}.
CC   -!- TISSUE SPECIFICITY: Expressed predominantly in the hippocampal region
CC       of the brain and in kidney. Lower levels in the ovary, testis and
CC       mandibular gland.
CC   -!- DOMAIN: The NAALADase activity is found in the central region, the
CC       dipeptidyl peptidase IV type activity in the C-terminal.
CC   -!- SIMILARITY: Belongs to the peptidase M28 family. M28B subfamily.
CC       {ECO:0000305}.
CC   -!- CAUTION: There are amino acid differences between the sequence shown in
CC       fig.1 (PubMed:11210180) and the sequence deposited in the database
CC       (AF026380). The sequence from fig.1 shows only 3 conflicts between
CC       PubMed:11210180 and PubMed:16141072. These are at AA positions 141, 240
CC       and 287. {ECO:0000305|PubMed:11210180}.
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DR   EMBL; AF026380; AAB81971.1; -; mRNA.
DR   EMBL; AK002920; BAB22457.1; -; mRNA.
DR   EMBL; BC119605; AAI19606.1; -; mRNA.
DR   CCDS; CCDS21436.1; -.
DR   RefSeq; NP_001153178.1; NM_001159706.1.
DR   RefSeq; NP_058050.3; NM_016770.3.
DR   AlphaFoldDB; O35409; -.
DR   SMR; O35409; -.
DR   STRING; 10090.ENSMUSP00000001824; -.
DR   MEROPS; M28.010; -.
DR   GlyConnect; 2340; 7 N-Linked glycans (6 sites).
DR   GlyCosmos; O35409; 9 sites, 7 glycans.
DR   GlyGen; O35409; 10 sites, 7 N-linked glycans (6 sites), 1 O-linked glycan (1 site).
DR   iPTMnet; O35409; -.
DR   PhosphoSitePlus; O35409; -.
DR   jPOST; O35409; -.
DR   MaxQB; O35409; -.
DR   PaxDb; 10090-ENSMUSP00000001824; -.
DR   PeptideAtlas; O35409; -.
DR   ProteomicsDB; 271789; -.
DR   Antibodypedia; 2262; 1480 antibodies from 41 providers.
DR   DNASU; 53320; -.
DR   Ensembl; ENSMUST00000001824.7; ENSMUSP00000001824.6; ENSMUSG00000001773.15.
DR   GeneID; 53320; -.
DR   KEGG; mmu:53320; -.
DR   UCSC; uc009ifh.2; mouse.
DR   AGR; MGI:1858193; -.
DR   CTD; 2346; -.
DR   MGI; MGI:1858193; Folh1.
DR   VEuPathDB; HostDB:ENSMUSG00000001773; -.
DR   eggNOG; KOG2195; Eukaryota.
DR   GeneTree; ENSGT01030000234598; -.
DR   InParanoid; O35409; -.
DR   OMA; NVVIASW; -.
DR   OrthoDB; 2428249at2759; -.
DR   PhylomeDB; O35409; -.
DR   TreeFam; TF312981; -.
DR   BRENDA; 3.4.17.21; 3474.
DR   Reactome; R-MMU-8963693; Aspartate and asparagine metabolism.
DR   BioGRID-ORCS; 53320; 4 hits in 81 CRISPR screens.
DR   PRO; PR:O35409; -.
DR   Proteomes; UP000000589; Chromosome 7.
DR   RNAct; O35409; Protein.
DR   Bgee; ENSMUSG00000001773; Expressed in right kidney and 63 other cell types or tissues.
DR   ExpressionAtlas; O35409; baseline and differential.
DR   GO; GO:0009986; C:cell surface; ISO:MGI.
DR   GO; GO:0016020; C:membrane; IDA:MGI.
DR   GO; GO:0005886; C:plasma membrane; IDA:MGI.
DR   GO; GO:1904492; F:Ac-Asp-Glu binding; ISO:MGI.
DR   GO; GO:0004180; F:carboxypeptidase activity; IDA:MGI.
DR   GO; GO:0016805; F:dipeptidase activity; IDA:MGI.
DR   GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR   GO; GO:0004181; F:metallocarboxypeptidase activity; ISO:MGI.
DR   GO; GO:0008233; F:peptidase activity; IDA:MGI.
DR   GO; GO:1904493; F:tetrahydrofolyl-poly(glutamate) polymer binding; ISO:MGI.
DR   GO; GO:0006760; P:folic acid-containing compound metabolic process; IDA:MGI.
DR   GO; GO:0043065; P:positive regulation of apoptotic process; ISO:MGI.
DR   GO; GO:0030163; P:protein catabolic process; ISO:MGI.
DR   GO; GO:0006508; P:proteolysis; IDA:MGI.
DR   CDD; cd08022; M28_PSMA_like; 1.
DR   CDD; cd02121; PA_GCPII_like; 1.
DR   Gene3D; 3.50.30.30; -; 1.
DR   Gene3D; 1.20.930.40; Transferrin receptor-like, dimerisation domain; 1.
DR   Gene3D; 3.40.630.10; Zn peptidases; 1.
DR   InterPro; IPR046450; PA_dom_sf.
DR   InterPro; IPR003137; PA_domain.
DR   InterPro; IPR007484; Peptidase_M28.
DR   InterPro; IPR039373; Peptidase_M28B.
DR   InterPro; IPR007365; TFR-like_dimer_dom.
DR   InterPro; IPR036757; TFR-like_dimer_dom_sf.
DR   PANTHER; PTHR10404:SF36; GLUTAMATE CARBOXYPEPTIDASE 2; 1.
DR   PANTHER; PTHR10404; N-ACETYLATED-ALPHA-LINKED ACIDIC DIPEPTIDASE; 1.
DR   Pfam; PF02225; PA; 1.
DR   Pfam; PF04389; Peptidase_M28; 1.
DR   Pfam; PF04253; TFR_dimer; 1.
DR   SUPFAM; SSF52025; PA domain; 1.
DR   SUPFAM; SSF47672; Transferrin receptor-like dimerisation domain; 1.
DR   SUPFAM; SSF53187; Zn-dependent exopeptidases; 1.
DR   Genevisible; O35409; MM.
PE   1: Evidence at protein level;
KW   Calcium; Carboxypeptidase; Cell membrane; Dipeptidase; Glycoprotein;
KW   Hydrolase; Membrane; Metal-binding; Metalloprotease;
KW   Multifunctional enzyme; Phosphoprotein; Protease; Reference proteome;
KW   Signal-anchor; Transmembrane; Transmembrane helix; Zinc.
FT   CHAIN           1..752
FT                   /note="Glutamate carboxypeptidase 2"
FT                   /id="PRO_0000174118"
FT   TOPO_DOM        1..22
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        23..44
FT                   /note="Helical; Signal-anchor for type II membrane protein"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        45..752
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   REGION          276..589
FT                   /note="NAALADase"
FT   ACT_SITE        426
FT                   /note="Nucleophile; for NAALADase activity"
FT                   /evidence="ECO:0000250"
FT   ACT_SITE        630
FT                   /note="Charge relay system"
FT                   /evidence="ECO:0000255"
FT   ACT_SITE        668
FT                   /note="Charge relay system"
FT                   /evidence="ECO:0000255"
FT   ACT_SITE        691
FT                   /note="Charge relay system"
FT                   /evidence="ECO:0000255"
FT   BINDING         212
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:Q9Y3Q0"
FT   BINDING         259
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:Q9Y3Q0"
FT   BINDING         271
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /evidence="ECO:0000250|UniProtKB:Q04609"
FT   BINDING         274
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /evidence="ECO:0000250|UniProtKB:Q04609"
FT   BINDING         379
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="1"
FT                   /ligand_note="catalytic"
FT                   /evidence="ECO:0000250|UniProtKB:Q9Y3Q0"
FT   BINDING         389
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="1"
FT                   /ligand_note="catalytic"
FT                   /evidence="ECO:0000250|UniProtKB:Q9Y3Q0"
FT   BINDING         389
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000250|UniProtKB:Q04609"
FT   BINDING         426
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:Q9Y3Q0"
FT   BINDING         427
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000250|UniProtKB:Q04609"
FT   BINDING         435
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /evidence="ECO:0000250|UniProtKB:Q04609"
FT   BINDING         438
FT                   /ligand="Ca(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29108"
FT                   /evidence="ECO:0000250|UniProtKB:Q04609"
FT   BINDING         455
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="1"
FT                   /ligand_note="catalytic"
FT                   /evidence="ECO:0000250|UniProtKB:Q9Y3Q0"
FT   BINDING         519..520
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:Q9Y3Q0"
FT   BINDING         521
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:Q04609"
FT   BINDING         536..538
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:Q04609"
FT   BINDING         554..555
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:Q9Y3Q0"
FT   BINDING         554
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:Q04609"
FT   BINDING         555
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000250|UniProtKB:Q04609"
FT   BINDING         701..702
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:Q9Y3Q0"
FT   MOD_RES         10
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P70627"
FT   CARBOHYD        78
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000250|UniProtKB:Q04609"
FT   CARBOHYD        123
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000250|UniProtKB:Q04609"
FT   CARBOHYD        155
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000250|UniProtKB:Q04609"
FT   CARBOHYD        338
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000250|UniProtKB:Q04609"
FT   CARBOHYD        461
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000250|UniProtKB:Q04609"
FT   CARBOHYD        478
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000250|UniProtKB:Q04609"
FT   CARBOHYD        615
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        640
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000250|UniProtKB:Q04609"
FT   CARBOHYD        722
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CONFLICT        141
FT                   /note="F -> S (in Ref. 2; BAB22457)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        178
FT                   /note="Y -> F (in Ref. 1; AAB81971)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        219
FT                   /note="A -> V (in Ref. 1; AAB81971)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        240
FT                   /note="A -> G (in Ref. 1; AAB81971)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        287
FT                   /note="N -> E (in Ref. 1; AAB81971)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        583
FT                   /note="G -> R (in Ref. 1; AAB81971)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        625
FT                   /note="K -> E (in Ref. 1; AAB81971)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        728
FT                   /note="N -> S (in Ref. 1; AAB81971)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        749
FT                   /note="R -> M (in Ref. 1; AAB81971)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   752 AA;  84574 MW;  F96041949214E8F3 CRC64;
     MWNALQDRDS AEVLGHRQRW LRVGTLVLAL TGTFLIGFLF GWFIKPSNEA TGNVSHSGMK
     KEFLHELKAE NIKKFLYNFT RTPHLAGTQN NFELAKQIHD QWKEFGLDLV ELSHYDVLLS
     YPNKTHPNYI SIINEDGNEI FKTSLSEQPP PGYENISDVV PPYSAFSPQG TPEGDLVYVN
     YARTEDFFKL EREMKISCSG KIVIARYGKV FRGNMVKNAQ LAGAKGMILY SDPADYFVPA
     VKSYPDGWNL PGGGVQRGNV LNLNGAGDPL TPGYPANEHA YRHELTNAVG LPSIPVHPIG
     YDDAQKLLEH MGGPAPPDSS WKGGLKVPYN VGPGFAGNFS TQKVKMHIHS YTKVTRIYNV
     IGTLKGALEP DRYVILGGHR DAWVFGGIDP QSGAAVVHEI VRSFGTLKKK GRRPRRTILF
     ASWDAEEFGL LGSTEWAEEH SRLLQERGVA YINADSSIEG NYTLRVDCTP LMYSLVYNLT
     KELQSPDEGF EGKSLYDSWK EKSPSPEFIG MPRISKLGSG NDFEVFFQRL GIASGRARYT
     KNWKTNKVSS YPLYHSVYET YELVVKFYDP TFKYHLTVAQ VRGAMVFELA NSIVLPFDCQ
     SYAVALKKYA DTIYNISMKH PQEMKAYMIS FDSLFSAVNN FTDVASKFNQ RLQELDKSNP
     ILLRIMNDQL MYLERAFIDP LGLPGRPFYR HIIYAPSSHN KYAGESFPGI YDALFDISSK
     VNASKAWNEV KRQISIATFT VQAAAETLRE VA
//