GREM2_MOUSE
ID GREM2_MOUSE Reviewed; 168 AA.
AC O88273;
DT 12-APR-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1998, sequence version 1.
DT 03-AUG-2022, entry version 124.
DE RecName: Full=Gremlin-2;
DE AltName: Full=Cysteine knot superfamily 1, BMP antagonist 2;
DE AltName: Full=Protein related to DAN and cerberus;
DE Short=PRDC;
DE Flags: Precursor;
GN Name=Grem2; Synonyms=Cktsf1b2, Prdc;
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], AND DEVELOPMENTAL STAGE.
RC STRAIN=C57BL/6J; TISSUE=CNS;
RX PubMed=9639362; DOI=10.1046/j.1440-169x.1998.t01-1-00010.x;
RA Minabe-Saegusa C., Saegusa H., Tsukahara M., Noguchi S.;
RT "Sequence and expression of a novel mouse gene PRDC (protein related to DAN
RT and cerberus) identified by a gene trap approach.";
RL Dev. Growth Differ. 40:343-353(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Head;
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 [3]
RP FUNCTION, INTERACTION WITH BMP2 AND BMP4, TISSUE SPECIFICITY, AND
RP INDUCTION.
RX PubMed=15039429; DOI=10.1074/jbc.m402376200;
RA Sudo S., Avsian-Kretchmer O., Wang L.S., Hsueh A.J.;
RT "Protein related to DAN and cerberus is a bone morphogenetic protein
RT antagonist that participates in ovarian paracrine regulation.";
RL J. Biol. Chem. 279:23134-23141(2004).
RN [4]
RP FUNCTION, INTERACTION WITH BMP2; BMP4 AND BMP7, MUTAGENESIS OF CYS-120,
RP SUBUNIT, GLYCOSYLATION, AND IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=23063586; DOI=10.1016/j.jmb.2012.10.003;
RA Kattamuri C., Luedeke D.M., Nolan K., Rankin S.A., Greis K.D., Zorn A.M.,
RA Thompson T.B.;
RT "Members of the DAN family are BMP antagonists that form highly stable
RT noncovalent dimers.";
RL J. Mol. Biol. 424:313-327(2012).
RN [5]
RP DEVELOPMENTAL STAGE.
RX PubMed=26416033; DOI=10.1177/0022034515608168;
RA Kantaputra P.N., Kaewgahya M., Hatsadaloi A., Vogel P., Kawasaki K.,
RA Ohazama A., Ketudat Cairns J.R.;
RT "GREMLIN 2 mutations and dental anomalies.";
RL J. Dent. Res. 94:1646-1652(2015).
RN [6]
RP X-RAY CRYSTALLOGRAPHY (2.25 ANGSTROMS) OF 22-168, FUNCTION, SUBUNIT,
RP INTERACTION WITH BMP2 AND BMP4, HEPARIN-BINDING, MUTAGENESIS OF LEU-68;
RP TRP-72; PHE-96; TYR-98; PHE-104; TYR-105 AND PHE-117, AND DISULFIDE BONDS.
RX PubMed=23850456; DOI=10.1016/j.str.2013.06.005;
RA Nolan K., Kattamuri C., Luedeke D.M., Deng X., Jagpal A., Zhang F.,
RA Linhardt R.J., Kenny A.P., Zorn A.M., Thompson T.B.;
RT "Structure of protein related to Dan and Cerberus: insights into the
RT mechanism of bone morphogenetic protein antagonism.";
RL Structure 21:1417-1429(2013).
CC -!- FUNCTION: Cytokine that inhibits the activity of BMP2 and BMP4 in a
CC dose-dependent manner, and thereby modulates signaling by BMP family
CC members. Contributes to the regulation of embryonic morphogenesis via
CC BMP family members. Antagonizes BMP4-induced suppression of
CC progesterone production in granulosa cells.
CC {ECO:0000269|PubMed:15039429, ECO:0000269|PubMed:23063586,
CC ECO:0000269|PubMed:23850456}.
CC -!- SUBUNIT: Homodimer. Interacts with BMP2, BMP4 and BMP7, but has lower
CC affinity for BMP7 than for BMP2 and BMP4. Binds heparin; this impairs
CC the interaction with BMP2. {ECO:0000269|PubMed:15039429,
CC ECO:0000269|PubMed:23063586, ECO:0000269|PubMed:23850456}.
CC -!- INTERACTION:
CC O88273; O88273: Grem2; NbExp=3; IntAct=EBI-16064759, EBI-16064759;
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000305}.
CC -!- TISSUE SPECIFICITY: Highly expressed in the ovary, followed by brain,
CC spleen, colon, kidney and uterus. In ovary expressed in granulosa cells
CC of selective early antral follicles. {ECO:0000269|PubMed:15039429}.
CC -!- DEVELOPMENTAL STAGE: Expressed in commissural neurons in the developing
CC spinal cord (PubMed:9639362). Expressed during the development of teeth
CC and hair follicles (PubMed:26416033). {ECO:0000269|PubMed:26416033,
CC ECO:0000269|PubMed:9639362}.
CC -!- INDUCTION: Up-regulated by gonadotropin treatment.
CC {ECO:0000269|PubMed:15039429}.
CC -!- PTM: N-glycosylated. {ECO:0000269|PubMed:23063586}.
CC -!- SIMILARITY: Belongs to the DAN family. {ECO:0000305}.
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DR EMBL; AB011030; BAA29038.1; -; mRNA.
DR EMBL; BC079905; AAH79905.1; -; mRNA.
DR CCDS; CCDS15545.1; -.
DR RefSeq; NP_035955.1; NM_011825.1.
DR RefSeq; XP_006496889.1; XM_006496826.3.
DR RefSeq; XP_017175937.1; XM_017320448.1.
DR PDB; 4JPH; X-ray; 2.25 A; A/B/C/D=22-168.
DR PDB; 5HK5; X-ray; 2.90 A; E/F/G/H=22-168.
DR PDBsum; 4JPH; -.
DR PDBsum; 5HK5; -.
DR AlphaFoldDB; O88273; -.
DR SMR; O88273; -.
DR DIP; DIP-60475N; -.
DR IntAct; O88273; 2.
DR STRING; 10090.ENSMUSP00000049640; -.
DR GlyGen; O88273; 2 sites.
DR iPTMnet; O88273; -.
DR PhosphoSitePlus; O88273; -.
DR jPOST; O88273; -.
DR PaxDb; O88273; -.
DR PeptideAtlas; O88273; -.
DR PRIDE; O88273; -.
DR ProteomicsDB; 271296; -.
DR Antibodypedia; 4089; 164 antibodies from 29 providers.
DR Ensembl; ENSMUST00000055294; ENSMUSP00000049640; ENSMUSG00000050069.
DR GeneID; 23893; -.
DR KEGG; mmu:23893; -.
DR UCSC; uc007dtf.1; mouse.
DR CTD; 64388; -.
DR MGI; MGI:1344367; Grem2.
DR VEuPathDB; HostDB:ENSMUSG00000050069; -.
DR eggNOG; ENOG502QZFW; Eukaryota.
DR GeneTree; ENSGT00940000154209; -.
DR HOGENOM; CLU_101024_2_0_1; -.
DR InParanoid; O88273; -.
DR OMA; MIWKFAV; -.
DR OrthoDB; 1270652at2759; -.
DR PhylomeDB; O88273; -.
DR TreeFam; TF106445; -.
DR Reactome; R-MMU-201451; Signaling by BMP.
DR BioGRID-ORCS; 23893; 3 hits in 71 CRISPR screens.
DR ChiTaRS; Grem2; mouse.
DR PRO; PR:O88273; -.
DR Proteomes; UP000000589; Chromosome 1.
DR RNAct; O88273; protein.
DR Bgee; ENSMUSG00000050069; Expressed in paneth cell and 170 other tissues.
DR ExpressionAtlas; O88273; baseline and differential.
DR Genevisible; O88273; MM.
DR GO; GO:0005615; C:extracellular space; IMP:UniProtKB.
DR GO; GO:0036122; F:BMP binding; IMP:UniProtKB.
DR GO; GO:0005125; F:cytokine activity; IEA:UniProtKB-KW.
DR GO; GO:0008201; F:heparin binding; IDA:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; IMP:UniProtKB.
DR GO; GO:0048018; F:receptor ligand activity; IBA:GO_Central.
DR GO; GO:0009887; P:animal organ morphogenesis; IBA:GO_Central.
DR GO; GO:0019221; P:cytokine-mediated signaling pathway; IMP:UniProtKB.
DR GO; GO:0048263; P:determination of dorsal identity; IMP:UniProtKB.
DR GO; GO:0010172; P:embryonic body morphogenesis; IMP:UniProtKB.
DR GO; GO:0030514; P:negative regulation of BMP signaling pathway; IMP:UniProtKB.
DR GO; GO:0060300; P:regulation of cytokine activity; IMP:UniProtKB.
DR GO; GO:0038098; P:sequestering of BMP from receptor via BMP binding; IMP:UniProtKB.
DR Gene3D; 2.10.90.10; -; 1.
DR InterPro; IPR006207; Cys_knot_C.
DR InterPro; IPR029034; Cystine-knot_cytokine.
DR InterPro; IPR004133; DAN.
DR InterPro; IPR017159; Gremlin-1/2.
DR Pfam; PF03045; DAN; 1.
DR PIRSF; PIRSF037254; Gremlin_precursor; 1.
DR SMART; SM00041; CT; 1.
DR PROSITE; PS01225; CTCK_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cytokine; Developmental protein; Disulfide bond;
KW Glycoprotein; Heparin-binding; Reference proteome; Secreted; Signal.
FT SIGNAL 1..21
FT /evidence="ECO:0000255"
FT CHAIN 22..168
FT /note="Gremlin-2"
FT /id="PRO_0000006721"
FT DOMAIN 73..163
FT /note="CTCK"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00039"
FT CARBOHYD 40
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 161
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 73..123
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00039,
FT ECO:0000269|PubMed:23850456"
FT DISULFID 87..137
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00039,
FT ECO:0000269|PubMed:23850456"
FT DISULFID 97..155
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00039,
FT ECO:0000269|PubMed:23850456"
FT DISULFID 101..157
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00039,
FT ECO:0000269|PubMed:23850456"
FT MUTAGEN 68
FT /note="L->A: Slightly reduces affinity for BMP2 and BMP4.
FT No effect on inhibition of BMP2 signaling."
FT /evidence="ECO:0000269|PubMed:23850456"
FT MUTAGEN 72
FT /note="W->A: Strongly reduces affinity for BMP2 and BMP4.
FT Reduces inhibition of BMP2 signaling."
FT /evidence="ECO:0000269|PubMed:23850456"
FT MUTAGEN 96
FT /note="F->A: Reduces affinity for BMP2 and BMP4. Reduces
FT inhibition of BMP2 signaling."
FT /evidence="ECO:0000269|PubMed:23850456"
FT MUTAGEN 98
FT /note="Y->A: Strongly reduces affinity for BMP2 and BMP4.
FT Strongly reduces inhibition of BMP2 signaling."
FT /evidence="ECO:0000269|PubMed:23850456"
FT MUTAGEN 104
FT /note="F->A: Reduces affinity for BMP2 and BMP4. Strongly
FT reduces inhibition of BMP2 signaling."
FT /evidence="ECO:0000269|PubMed:23850456"
FT MUTAGEN 105
FT /note="Y->A: Strongly reduces affinity for BMP2 and BMP4.
FT Strongly reduces inhibition of BMP2 signaling."
FT /evidence="ECO:0000269|PubMed:23850456"
FT MUTAGEN 117
FT /note="F->A: Strongly reduces affinity for BMP2 and BMP4.
FT Strongly reduces inhibition of BMP2 signaling."
FT /evidence="ECO:0000269|PubMed:23850456"
FT MUTAGEN 120
FT /note="C->S: No effect on dimerization. No effect on
FT inhibition of BMP signaling."
FT /evidence="ECO:0000269|PubMed:23063586"
FT HELIX 49..53
FT /evidence="ECO:0007829|PDB:4JPH"
FT HELIX 57..62
FT /evidence="ECO:0007829|PDB:4JPH"
FT HELIX 65..68
FT /evidence="ECO:0007829|PDB:4JPH"
FT STRAND 72..82
FT /evidence="ECO:0007829|PDB:4JPH"
FT STRAND 90..107
FT /evidence="ECO:0007829|PDB:4JPH"
FT STRAND 110..113
FT /evidence="ECO:0007829|PDB:4JPH"
FT STRAND 116..120
FT /evidence="ECO:0007829|PDB:4JPH"
FT STRAND 122..136
FT /evidence="ECO:0007829|PDB:4JPH"
FT STRAND 140..158
FT /evidence="ECO:0007829|PDB:4JPH"
SQ SEQUENCE 168 AA; 19334 MW; 6361C1581D49C281 CRC64;
MFWKLSLTLL LVAVLVKVAE TRKNRPAGAI PSPYKDGSSN NSERWHHQIK EVLASSQEAL
VVTERKYLKS DWCKTQPLRQ TVSEEGCRSR TILNRFCYGQ CNSFYIPRHV KKEEDSFQSC
AFCKPQRVTS VIVELECPGL DPPFRIKKIQ KVKHCRCMSV NLSDSDKQ
