Linked Life Data

18160401

Source:http://linkedlifedata.com/resource/pubmed/id/18160401

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
9
pubmed:dateCreated
2008-2-25
pubmed:databankReference
pubmed:abstractText
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.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
29
pubmed:volume
283
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
5876-87
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:18160401-Adenomatous Polyposis Coli, pubmed-meshheading:18160401-Adult, pubmed-meshheading:18160401-Binding Sites, pubmed-meshheading:18160401-Bone Morphogenetic Protein 2, pubmed-meshheading:18160401-Bone Morphogenetic Protein Receptors, Type I, pubmed-meshheading:18160401-Bone Morphogenetic Protein Receptors, Type II, pubmed-meshheading:18160401-Bone Morphogenetic Proteins, pubmed-meshheading:18160401-Colon, pubmed-meshheading:18160401-Embryonic Development, pubmed-meshheading:18160401-Enterocytes, pubmed-meshheading:18160401-Epitopes, pubmed-meshheading:18160401-Homeostasis, pubmed-meshheading:18160401-Humans, pubmed-meshheading:18160401-Ligands, pubmed-meshheading:18160401-Mutation, pubmed-meshheading:18160401-Protein Binding, pubmed-meshheading:18160401-Protein Structure, Quaternary, pubmed-meshheading:18160401-Protein Structure, Tertiary, pubmed-meshheading:18160401-Signal Transduction, pubmed-meshheading:18160401-Structure-Activity Relationship, pubmed-meshheading:18160401-Transforming Growth Factor beta, pubmed-meshheading:18160401-Tumor Suppressor Proteins
pubmed:year
2008
pubmed:articleTitle
Structure analysis of bone morphogenetic protein-2 type I receptor complexes reveals a mechanism of receptor inactivation in juvenile polyposis syndrome.
pubmed:affiliation
Lehrstuhl für Botanik I-Molekulare Pflanzenphysiologie und Biophysik, Julius-von-Sachs-Institut der Universität Würzburg, Julius-von-Sachs-Platz 2, D-97082 Würzburg, Germany.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't