FOLH1_MOUSE
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 03-AUG-2022, entry version 171.
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}.
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; 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 GlyGen; O35409; 9 sites, 7 N-linked glycans (6 sites).
DR iPTMnet; O35409; -.
DR PhosphoSitePlus; O35409; -.
DR jPOST; O35409; -.
DR MaxQB; O35409; -.
DR PaxDb; O35409; -.
DR PeptideAtlas; O35409; -.
DR PRIDE; O35409; -.
DR ProteomicsDB; 271789; -.
DR Antibodypedia; 2262; 1236 antibodies from 41 providers.
DR DNASU; 53320; -.
DR Ensembl; ENSMUST00000001824; ENSMUSP00000001824; ENSMUSG00000001773.
DR GeneID; 53320; -.
DR KEGG; mmu:53320; -.
DR UCSC; uc009ifh.2; mouse.
DR CTD; 2346; -.
DR MGI; MGI:1858193; Folh1.
DR VEuPathDB; HostDB:ENSMUSG00000001773; -.
DR eggNOG; KOG2195; Eukaryota.
DR GeneTree; ENSGT01030000234598; -.
DR InParanoid; O35409; -.
DR OMA; VFAPGIW; -.
DR OrthoDB; 804230at2759; -.
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; 3 hits in 76 CRISPR screens.
DR PRO; PR:O35409; -.
DR Proteomes; UP000000589; Chromosome 7.
DR RNAct; O35409; protein.
DR Bgee; ENSMUSG00000001773; Expressed in right kidney and 62 other tissues.
DR ExpressionAtlas; O35409; baseline and differential.
DR Genevisible; O35409; MM.
DR GO; GO:0009986; C:cell surface; ISO:MGI.
DR GO; GO:0016021; C:integral component of membrane; IDA:MGI.
DR GO; GO:0005887; C:integral component of plasma membrane; IDA:MGI.
DR GO; GO:0005886; C:plasma membrane; ISO: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:0035609; P:C-terminal protein deglutamylation; IEA:Ensembl.
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 Gene3D; 1.20.930.40; -; 1.
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; PTHR10404; 1.
DR Pfam; PF02225; PA; 1.
DR Pfam; PF04389; Peptidase_M28; 1.
DR Pfam; PF04253; TFR_dimer; 1.
DR SUPFAM; SSF47672; SSF47672; 1.
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
