FOLH1_RAT
ID FOLH1_RAT Reviewed; 752 AA.
AC P70627; Q547B6;
DT 11-FEB-2002, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-1997, sequence version 1.
DT 03-AUG-2022, entry version 144.
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=Naalad1;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=Sprague-Dawley; TISSUE=Hippocampus;
RX PubMed=9375657; DOI=10.1046/j.1471-4159.1997.69062270.x;
RA Bzdega T., Turi T., Wroblewska B., She D., Chung H.S., Kim H., Neale J.H.;
RT "Molecular cloning of a peptidase against N-acetylaspartylglutamate from a
RT rat hippocampal cDNA library.";
RL J. Neurochem. 69:2270-2277(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=Sprague-Dawley; TISSUE=Brain;
RX PubMed=9501243; DOI=10.1073/pnas.95.6.3215;
RA Luthi-Carter R., Berger U.V., Barczak A.K., Enna M., Coyle J.T.;
RT "Isolation and expression of a rat brain cDNA encoding glutamate
RT carboxypeptidase II.";
RL Proc. Natl. Acad. Sci. U.S.A. 95:3215-3220(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=Sprague-Dawley; TISSUE=Adipose tissue;
RX PubMed=15019832; DOI=10.1016/j.abb.2004.01.011;
RA Park S.Y., Ha B.G., Choi G.H., Lee W.;
RT "N-Acetylated alpha-linked acidic dipeptidase expressed in rat adipocytes
RT is localized in the insulin-responsive glucose transporter (GLUT4)
RT intracellular compartments and involved in the insulin-stimulated GLUT4
RT recruitment.";
RL Arch. Biochem. Biophys. 424:11-22(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 284-752.
RC TISSUE=Brain;
RX PubMed=8570628; DOI=10.1073/pnas.93.2.749;
RA Carter R.E., Feldman A.R., Coyle J.T.;
RT "Prostate-specific membrane antigen is a hydrolase with substrate and
RT pharmacologic characteristics of a neuropeptidase.";
RL Proc. Natl. Acad. Sci. U.S.A. 93:749-753(1996).
RN [5]
RP ALTERNATIVE SPLICING.
RA Bzdega T., She D., Turi T., Wroblewska B., Neale J.H.;
RT "Molecular cloning of alternatively spliced variants of the peptidase
RT against N-acetylaspartylglutamate (NAAG) from human and rat nervous
RT systems.";
RL Abstr. - Soc. Neurosci. 24:579-579(1998).
RN [6]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-10, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
RN [7]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-478 AND ASN-615, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain;
RX PubMed=24090084; DOI=10.1021/pr400783j;
RA Parker B.L., Thaysen-Andersen M., Solis N., Scott N.E., Larsen M.R.,
RA Graham M.E., Packer N.H., Cordwell S.J.;
RT "Site-specific glycan-peptide analysis for determination of N-glycoproteome
RT heterogeneity.";
RL J. Proteome Res. 12:5791-5800(2013).
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 activity is inhibited by beta-NAAG,
CC quisqualic acid and 2-(phosphonomethyl)glutaric acid (PMG).
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 -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Comment=Experimental confirmation may be lacking for some isoforms.;
CC Name=1;
CC IsoId=P70627-1; Sequence=Displayed;
CC Name=2; Synonyms=Short form;
CC IsoId=P70627-2; Sequence=Not described;
CC Name=3; Synonyms=Long form;
CC IsoId=P70627-3; Sequence=Not described;
CC -!- TISSUE SPECIFICITY: Widely expressed throughout brain regions with
CC highest levels in the hippocampus, dentate gyrus, priform cortex,
CC choroid plexus of ventricles, pineal gland, anterior lobe of the
CC pituitary gland and supraoptic nucleus. High levels also found in the
CC cerebral cortex, substantia nigra, pontine nucleus and the granule cell
CC layer of cerebellum. Highly expressed in astrocytes and non-myelinating
CC Schwann cells. Also expressed in kidney, localizing to the proximal
CC brush border of the renal tube.
CC -!- DOMAIN: The NAALADase activity is found in the central region, the
CC dipeptidyl peptidase IV type activity in the C-terminal.
CC -!- MISCELLANEOUS: [Isoform 2]: Probably inactive. {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the peptidase M28 family. M28B subfamily.
CC {ECO:0000305}.
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DR EMBL; U75973; AAC53423.1; -; mRNA.
DR EMBL; AF040256; AAC40067.1; -; mRNA.
DR EMBL; AF513486; AAM47015.1; -; mRNA.
DR EMBL; AF039707; AAB96759.1; -; mRNA.
DR RefSeq; NP_476533.1; NM_057185.2. [P70627-1]
DR AlphaFoldDB; P70627; -.
DR SMR; P70627; -.
DR STRING; 10116.ENSRNOP00000018592; -.
DR BindingDB; P70627; -.
DR ChEMBL; CHEMBL5098; -.
DR MEROPS; M28.010; -.
DR GlyGen; P70627; 10 sites, 14 N-linked glycans (3 sites).
DR iPTMnet; P70627; -.
DR PhosphoSitePlus; P70627; -.
DR PaxDb; P70627; -.
DR PRIDE; P70627; -.
DR GeneID; 85309; -.
DR KEGG; rno:85309; -.
DR UCSC; RGD:70963; rat. [P70627-1]
DR CTD; 2346; -.
DR RGD; 70963; Folh1.
DR eggNOG; KOG2195; Eukaryota.
DR InParanoid; P70627; -.
DR OrthoDB; 804230at2759; -.
DR PhylomeDB; P70627; -.
DR BRENDA; 3.4.17.21; 5301.
DR Reactome; R-RNO-8963693; Aspartate and asparagine metabolism.
DR PRO; PR:P70627; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0009986; C:cell surface; ISO:RGD.
DR GO; GO:0016021; C:integral component of membrane; ISO:RGD.
DR GO; GO:0005887; C:integral component of plasma membrane; ISO:RGD.
DR GO; GO:0005886; C:plasma membrane; ISO:RGD.
DR GO; GO:1904492; F:Ac-Asp-Glu binding; ISO:RGD.
DR GO; GO:0004180; F:carboxypeptidase activity; ISO:RGD.
DR GO; GO:0016805; F:dipeptidase activity; ISO:RGD.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0004181; F:metallocarboxypeptidase activity; ISO:RGD.
DR GO; GO:0008233; F:peptidase activity; ISO:RGD.
DR GO; GO:1904493; F:tetrahydrofolyl-poly(glutamate) polymer binding; ISO:RGD.
DR GO; GO:0035609; P:C-terminal protein deglutamylation; ISO:RGD.
DR GO; GO:0006760; P:folic acid-containing compound metabolic process; ISO:RGD.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IMP:RGD.
DR GO; GO:0030163; P:protein catabolic process; IDA:RGD.
DR GO; GO:0006508; P:proteolysis; ISO:RGD.
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 Alternative splicing; Calcium; Carboxypeptidase; Cell membrane;
KW Dipeptidase; Glycoprotein; Hydrolase; Membrane; Metal-binding;
KW Metalloprotease; Multifunctional enzyme; Phosphoprotein; Protease;
KW Reference proteome; Signal-anchor; Transmembrane; Transmembrane helix;
KW Zinc.
FT CHAIN 1..752
FT /note="Glutamate carboxypeptidase 2"
FT /id="PRO_0000174120"
FT TOPO_DOM 1..19
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 20..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:0007744|PubMed:22673903"
FT CARBOHYD 48
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
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 197
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:0007744|PubMed:24090084"
FT CARBOHYD 615
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0007744|PubMed:24090084"
FT CARBOHYD 640
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000250|UniProtKB:Q04609"
SQ SEQUENCE 752 AA; 84540 MW; 5C0915A3B9C71E41 CRC64;
MWNAQQDSDS AEALGRRQRW FCAGTLVLAF TGTFIIGFLF GWFIKPSNDS TSSVSYPGMK
KAFLQELKAE NIKKFLYNFT RTPHLAGTQH NFELAKQIHA QWKEFGLDLV ELSDYDVLLS
YPNKTHPNYI SIINEDGNEI FKTSLAELSP PGYENISDVV PPYSAFSPQG TPEGDLVYVN
YARTEDFFKL ERVMKINCSG KIVIARYGQV FRGNKVKNAQ LAGAKGIILY SDPADYFVPG
VKSYPDGWNL PGGGVQRGNV LNLNGAGDPL TPGYPANEYA YRHEFTEAVG LPSIPVHPIG
YDDAQKLLEH MGGSAPPDSS WKGGLKVPYN VGPGFAGNFS KQKVKLHIHS YNKVTRIYNV
IGTLKGAVEP DRYVILGGHR DAWVFGGIDP QSGAAVVHEI VRTFGTLKKK GWRPRRTILF
ASWDAEEFGL LGSTEWAEEH SRLLQERGVA YINADSSIEG NYTLRVDCTP LMHSLVYNLT
KELPSPDEGF EGKSLYDSWK EKSPSTEFIG MPRISKLGSG NDFEVFFQRL GIASGRARYT
KNWKNNKVSS YPLYHSVYET YELVEKFYDP TFKYHLTVAQ VRGAMVFELA NSIVLPFDCQ
SYAVALKKHA ETIYNISMNH PQEMKAYMIS FDSLFSAVNN FTDVASKFNQ RLQDLDKSNP
ILLRILNDQL MYLERAFIDP LGLPGRPFYR HIIYAPSSHN KYAGESFPGI YDALFDINNK
VDTSKAWREV KRQISIAAFT VQAAAETLRE VD
