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| | <StructureSection load='5aej' size='340' side='right'caption='[[5aej]], [[Resolution|resolution]] 1.90Å' scene=''> | | <StructureSection load='5aej' size='340' side='right'caption='[[5aej]], [[Resolution|resolution]] 1.90Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5aej]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5AEJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5AEJ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5aej]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5AEJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5AEJ FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.904Å</td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5aej FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5aej OCA], [http://pdbe.org/5aej PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5aej RCSB], [http://www.ebi.ac.uk/pdbsum/5aej PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5aej ProSAT]</span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5aej FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5aej OCA], [https://pdbe.org/5aej PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5aej RCSB], [https://www.ebi.ac.uk/pdbsum/5aej PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5aej ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/GREM1_HUMAN GREM1_HUMAN]] Hereditary mixed polyposis syndrome. The disease is caused by mutations affecting the gene represented in this entry. HMPS1 is caused by a duplication spanning the 3' end of the SCG5 gene and a region upstream of the GREM1 locus. This duplication is associated with increased allele-specific GREM1 expression that may cause reduced bone morphogenetic protein (BMP) pathway activity. This mechanism also underlies tumorigenesis in juvenile polyposis of the large bowel (PubMed:22561515).<ref>PMID:22561515</ref> | + | [https://www.uniprot.org/uniprot/GREM1_HUMAN GREM1_HUMAN] Hereditary mixed polyposis syndrome. The disease is caused by mutations affecting the gene represented in this entry. HMPS1 is caused by a duplication spanning the 3' end of the SCG5 gene and a region upstream of the GREM1 locus. This duplication is associated with increased allele-specific GREM1 expression that may cause reduced bone morphogenetic protein (BMP) pathway activity. This mechanism also underlies tumorigenesis in juvenile polyposis of the large bowel (PubMed:22561515).<ref>PMID:22561515</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/GREM1_HUMAN GREM1_HUMAN]] Cytokine that may play an important role during carcinogenesis and metanephric kidney organogenesis, as a BMP antagonist required for early limb outgrowth and patterning in maintaining the FGF4-SHH feedback loop. Down-regulates the BMP4 signaling in a dose-dependent manner. Acts as inhibitor of monocyte chemotaxis (By similarity).<ref>PMID:10894942</ref> | + | [https://www.uniprot.org/uniprot/GREM1_HUMAN GREM1_HUMAN] Cytokine that may play an important role during carcinogenesis and metanephric kidney organogenesis, as a BMP antagonist required for early limb outgrowth and patterning in maintaining the FGF4-SHH feedback loop. Down-regulates the BMP4 signaling in a dose-dependent manner. Acts as inhibitor of monocyte chemotaxis (By similarity).<ref>PMID:10894942</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Hyvonen, M]] | + | [[Category: Hyvonen M]] |
| - | [[Category: Kisonaite, M]] | + | [[Category: Kisonaite M]] |
| - | [[Category: Cystine knot]]
| + | |
| - | [[Category: Dan family]]
| + | |
| - | [[Category: Extracellular signalling]]
| + | |
| - | [[Category: Gremlin]]
| + | |
| - | [[Category: Growth factor]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Signaling]]
| + | |
| - | [[Category: Signaling protein]]
| + | |
| Structural highlights
Disease
GREM1_HUMAN Hereditary mixed polyposis syndrome. The disease is caused by mutations affecting the gene represented in this entry. HMPS1 is caused by a duplication spanning the 3' end of the SCG5 gene and a region upstream of the GREM1 locus. This duplication is associated with increased allele-specific GREM1 expression that may cause reduced bone morphogenetic protein (BMP) pathway activity. This mechanism also underlies tumorigenesis in juvenile polyposis of the large bowel (PubMed:22561515).[1]
Function
GREM1_HUMAN Cytokine that may play an important role during carcinogenesis and metanephric kidney organogenesis, as a BMP antagonist required for early limb outgrowth and patterning in maintaining the FGF4-SHH feedback loop. Down-regulates the BMP4 signaling in a dose-dependent manner. Acts as inhibitor of monocyte chemotaxis (By similarity).[2]
Publication Abstract from PubMed
Bone morphogenetic protein 2 (BMP-2) is a member of the transforming growth factor-beta (TGF-beta) signaling family and has a very broad biological role in development. Its signaling is regulated by many effectors: transmembrane proteins, membrane attached proteins and soluble secreted antagonists such as Gremlin-1. Very little is known about the molecular mechanism by which Gremlin-1 and other DAN family proteins inhibit BMP signaling. We analyzed the interaction of Gremlin-1 with BMP-2 using a range of biophysical techniques, and used mutagenesis to map the binding site on BMP-2. We have also determined the crystal structure of Gremlin-1, revealing a similar conserved dimeric structure as has been seen in other DAN family inhibitors. Measurements using biolayer interferometry indicate that Gremlin-1 and BMP-2 can form larger complexes, beyond the expected 1:1 stoichiometry of dimers, forming oligomers that assemble in alternating fashion. These results suggest that inhibition of BMP-2 by Gremlin-1 occurs by a mechanism that is distinct from other known inhibitors such as Noggin and Chordin and we propose a novel model of BMP-2/Gremlin-1 interaction yet not seen among any BMP antagonists, and cannot rule out that several different oligomeric states could be found, depending on the concentration of the two proteins.
Structure of Gremlin-1 and analysis of its interaction with BMP-2.,Kisonaite M, Wang X, Hyvonen M Biochem J. 2016 Apr 1. pii: BCJ20160254. PMID:27036124[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Jaeger E, Leedham S, Lewis A, Segditsas S, Becker M, Cuadrado PR, Davis H, Kaur K, Heinimann K, Howarth K, East J, Taylor J, Thomas H, Tomlinson I. Hereditary mixed polyposis syndrome is caused by a 40-kb upstream duplication that leads to increased and ectopic expression of the BMP antagonist GREM1. Nat Genet. 2012 May 6;44(6):699-703. doi: 10.1038/ng.2263. PMID:22561515 doi:http://dx.doi.org/10.1038/ng.2263
- ↑ Topol LZ, Modi WS, Koochekpour S, Blair DG. DRM/GREMLIN (CKTSF1B1) maps to human chromosome 15 and is highly expressed in adult and fetal brain. Cytogenet Cell Genet. 2000;89(1-2):79-84. PMID:10894942
- ↑ Kisonaite M, Wang X, Hyvonen M. Structure of Gremlin-1 and analysis of its interaction with BMP-2. Biochem J. 2016 Apr 1. pii: BCJ20160254. PMID:27036124 doi:http://dx.doi.org/10.1042/BCJ20160254
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