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2qja

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Revision as of 22:29, 11 September 2015

Crystal structure analysis of BMP-2 in complex with BMPR-IA variant B12

Structural highlights

2qja is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Related:	1rew, 1es7, 3bmp, 2qj9, 2qjb
Gene:	BMP2, BMP2A (HUMAN), BMPR1A, ACVRLK3, ALK3 (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum

Disease

[BMR1A_HUMAN] Defects in BMPR1A are a cause of juvenile polyposis syndrome (JPS) [MIM:174900]; also known as juvenile intestinal polyposis (JIP). JPS is an autosomal dominant gastrointestinal hamartomatous polyposis syndrome in which patients are at risk for developing gastrointestinal cancers. The lesions are typified by a smooth histological appearance, predominant stroma, cystic spaces and lack of a smooth muscle core. Multiple juvenile polyps usually occur in a number of Mendelian disorders. Sometimes, these polyps occur without associated features as in JPS; here, polyps tend to occur in the large bowel and are associated with an increased risk of colon and other gastrointestinal cancers.^[1] ^[2] ^[3] ^[4] ^[5] Defects in BMPR1A are a cause of Cowden disease (CD) [MIM:158350]. CD is an autosomal dominant cancer syndrome characterized by multiple hamartomas and by a high risk for breast, thyroid and endometrial cancers.^[6] ^[7] Defects in BMPR1A are the cause of hereditary mixed polyposis syndrome 2 (HMPS2) [MIM:610069]. Hereditary mixed polyposis syndrome (HMPS) is characterized by atypical juvenile polyps, colonic adenomas, and colorectal carcinomas.^[8] Note=A microdeletion of chromosome 10q23 involving BMPR1A and PTEN is a cause of chromosome 10q23 deletion syndrome, which shows overlapping features of the following three disorders: Bannayan-Zonana syndrome, Cowden disease and juvenile polyposis syndrome.^[9]

Function

[BMP2_HUMAN] Induces cartilage and bone formation. [BMR1A_HUMAN] On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. Receptor for BMP-2 and BMP-4.

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Bone morphogenetic proteins regulate many developmental processes during embryogenesis as well as tissue homeostasis in the adult. Signaling of bone morphogenetic proteins (BMPs) is accomplished by binding to two types of serine/threonine kinase transmembrane receptors termed type I and type II. Because a large number of ligands signal through a limited number of receptors, ligand-receptor interaction in the BMP superfamily is highly promiscuous, with a ligand binding to various receptors and a receptor binding many different BMP ligands. In this study we investigate the interaction of BMP-2 with its two high affinity type I receptors, BMP receptors IA (BMPR-IA) and BMPR-IB. Interestingly, 50% of the residues in the BMP-2 binding epitope of the BMPR-IA receptor are exchanged in BMPR-IB without a decrease in binding affinity or specificity for BMP-2. Our structural and functional analyses show that promiscuous binding of BMP-2 to both type I receptors is achieved by inherent backbone and side-chain flexibility as well as by variable hydration of the ligand-receptor interface enabling the BMP-2 surface to adapt to different receptor geometries. Despite the high degree of amino acid variability found in BMPR-IA and BMPR-IB binding equally to BMP-2, three single point missense mutations in the ectodomain of BMPR-IA cannot be tolerated. In juvenile polyposis syndrome these mutations have been shown to inactivate BMPR-IA. On the basis of our biochemical and biophysical analyses, we can show that the mutations, which are located outside the ligand binding epitope, alter the local or global fold of the receptor, thereby inactivating BMPR-IA and causing a loss of the BMP-2 tumor suppressor function in colon epithelial cells.

Structure analysis of bone morphogenetic protein-2 type I receptor complexes reveals a mechanism of receptor inactivation in juvenile polyposis syndrome.,Kotzsch A, Nickel J, Seher A, Heinecke K, van Geersdaele L, Herrmann T, Sebald W, Mueller TD J Biol Chem. 2008 Feb 29;283(9):5876-87. Epub 2007 Dec 26. PMID:18160401^[10]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Howe JR, Bair JL, Sayed MG, Anderson ME, Mitros FA, Petersen GM, Velculescu VE, Traverso G, Vogelstein B. Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis. Nat Genet. 2001 Jun;28(2):184-7. PMID:11381269 doi:10.1038/88919
↑ Zhou XP, Woodford-Richens K, Lehtonen R, Kurose K, Aldred M, Hampel H, Launonen V, Virta S, Pilarski R, Salovaara R, Bodmer WF, Conrad BA, Dunlop M, Hodgson SV, Iwama T, Jarvinen H, Kellokumpu I, Kim JC, Leggett B, Markie D, Mecklin JP, Neale K, Phillips R, Piris J, Rozen P, Houlston RS, Aaltonen LA, Tomlinson IP, Eng C. Germline mutations in BMPR1A/ALK3 cause a subset of cases of juvenile polyposis syndrome and of Cowden and Bannayan-Riley-Ruvalcaba syndromes. Am J Hum Genet. 2001 Oct;69(4):704-11. Epub 2001 Aug 30. PMID:11536076 doi:10.1086/323703
↑ Sayed MG, Ahmed AF, Ringold JR, Anderson ME, Bair JL, Mitros FA, Lynch HT, Tinley ST, Petersen GM, Giardiello FM, Vogelstein B, Howe JR. Germline SMAD4 or BMPR1A mutations and phenotype of juvenile polyposis. Ann Surg Oncol. 2002 Nov;9(9):901-6. PMID:12417513
↑ Friedl W, Uhlhaas S, Schulmann K, Stolte M, Loff S, Back W, Mangold E, Stern M, Knaebel HP, Sutter C, Weber RG, Pistorius S, Burger B, Propping P. Juvenile polyposis: massive gastric polyposis is more common in MADH4 mutation carriers than in BMPR1A mutation carriers. Hum Genet. 2002 Jul;111(1):108-11. Epub 2002 Jun 13. PMID:12136244 doi:10.1007/s00439-002-0748-9
↑ Kim IJ, Park JH, Kang HC, Kim KH, Kim JH, Ku JL, Kang SB, Park SY, Lee JS, Park JG. Identification of a novel BMPR1A germline mutation in a Korean juvenile polyposis patient without SMAD4 mutation. Clin Genet. 2003 Feb;63(2):126-30. PMID:12630959
↑ Howe JR, Bair JL, Sayed MG, Anderson ME, Mitros FA, Petersen GM, Velculescu VE, Traverso G, Vogelstein B. Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis. Nat Genet. 2001 Jun;28(2):184-7. PMID:11381269 doi:10.1038/88919
↑ Zhou XP, Woodford-Richens K, Lehtonen R, Kurose K, Aldred M, Hampel H, Launonen V, Virta S, Pilarski R, Salovaara R, Bodmer WF, Conrad BA, Dunlop M, Hodgson SV, Iwama T, Jarvinen H, Kellokumpu I, Kim JC, Leggett B, Markie D, Mecklin JP, Neale K, Phillips R, Piris J, Rozen P, Houlston RS, Aaltonen LA, Tomlinson IP, Eng C. Germline mutations in BMPR1A/ALK3 cause a subset of cases of juvenile polyposis syndrome and of Cowden and Bannayan-Riley-Ruvalcaba syndromes. Am J Hum Genet. 2001 Oct;69(4):704-11. Epub 2001 Aug 30. PMID:11536076 doi:10.1086/323703
↑ Howe JR, Bair JL, Sayed MG, Anderson ME, Mitros FA, Petersen GM, Velculescu VE, Traverso G, Vogelstein B. Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis. Nat Genet. 2001 Jun;28(2):184-7. PMID:11381269 doi:10.1038/88919
↑ Howe JR, Bair JL, Sayed MG, Anderson ME, Mitros FA, Petersen GM, Velculescu VE, Traverso G, Vogelstein B. Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis. Nat Genet. 2001 Jun;28(2):184-7. PMID:11381269 doi:10.1038/88919
↑ Kotzsch A, Nickel J, Seher A, Heinecke K, van Geersdaele L, Herrmann T, Sebald W, Mueller TD. Structure analysis of bone morphogenetic protein-2 type I receptor complexes reveals a mechanism of receptor inactivation in juvenile polyposis syndrome. J Biol Chem. 2008 Feb 29;283(9):5876-87. Epub 2007 Dec 26. PMID:18160401 doi:http://dx.doi.org/10.1074/jbc.M706029200

1 Structural highlights
2 Disease
3 Function
4 Evolutionary Conservation
5 Publication Abstract from PubMed
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2qja"

@@ Line 2: / Line 2: @@
 <StructureSection load='2qja' size='340' side='right' caption='[[2qja]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2qja]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2QJA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2QJA FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2qja]] 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=2QJA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2QJA FirstGlance]. <br>
 </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1rew|1rew]], [[1es7|1es7]], [[3bmp|3bmp]], [[2qj9|2qj9]], [[2qjb|2qjb]]</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BMP2, BMP2A ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]), BMPR1A, ACVRLK3, ALK3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BMP2, BMP2A ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), BMPR1A, ACVRLK3, ALK3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=2qja FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2qja OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2qja RCSB], [http://www.ebi.ac.uk/pdbsum/2qja PDBsum]</span></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=2qja FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2qja OCA], [http://pdbe.org/2qja PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2qja RCSB], [http://www.ebi.ac.uk/pdbsum/2qja PDBsum]</span></td></tr>
 </table>
 == Disease ==
@@ Line 29: / Line 29: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 2qja" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Homo sapiens]]
+[[Category: Human]]
 [[Category: Kotzsch, A]]
 [[Category: Mueller, T D]]

2qja

From Proteopedia

Revision as of 22:29, 11 September 2015

Crystal structure analysis of BMP-2 in complex with BMPR-IA variant B12

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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