Linked Life Data

20214400

Source:http://linkedlifedata.com/resource/pubmed/id/20214400

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
22
pubmed:dateCreated
2010-6-1
pubmed:abstractText
Natriuretic peptide receptor A (NPRA) is a noncovalent homodimeric receptor, composed of an extracellular domain (ECD) with a ligand-binding site, a single transmembrane domain (TM), and an intracellular domain (ICD) exhibiting guanylyl cyclase activity. NPRA activation by atrial natriuretic peptide (ANP) leads to cGMP production, which plays important roles in cardiovascular homeostasis. Initial studies have shown that activation of NPRA involves a conformational change in the juxtamembrane domain (JM). However, crystallographic study of the soluble ECD of NPRA has failed to document JM structure, and the conformational change involved in transmembrane signal transduction is still unknown. To analyze this conformational change, we first sequentially substituted nine amino acids of the JM with a cysteine residue. By studying the mutant's capacity to form ANP-induced or constitutive covalent disulfide dimers, we evaluated the relative proximity of JM residues, before and after NPRA activation. These results obtained with the full-length receptor demonstrate a high proximity of specific JM residues and are in disagreement with crystallography data. We also tested the hypothesis that signal transduction involves a TM rotation mechanism leading to ICD activation. By introducing one to five alanine residues into the TM alpha-helix, we show that a TM rotation of 40 degrees leads to constitutive NPRA activation. We finally studied the role of the TM in NPRA dimerization. By using the ToxR system, we demonstrate that the last JM residues are required to stabilize the TM dimer. Using these experimental data, we generated a new molecular model illustrating the active conformation of NPRA, where the JM and TM are depicted.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
1520-4995
pubmed:author
pubmed:issnType
Electronic
pubmed:day
8
pubmed:volume
49
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
4601-10
pubmed:meshHeading
pubmed-meshheading:20214400-Alanine, pubmed-meshheading:20214400-Amino Acid Substitution, pubmed-meshheading:20214400-Animals, pubmed-meshheading:20214400-Bacterial Proteins, pubmed-meshheading:20214400-Cell Line, pubmed-meshheading:20214400-Cysteine, pubmed-meshheading:20214400-DNA-Binding Proteins, pubmed-meshheading:20214400-Dimerization, pubmed-meshheading:20214400-Escherichia coli Proteins, pubmed-meshheading:20214400-Humans, pubmed-meshheading:20214400-Membrane Proteins, pubmed-meshheading:20214400-Models, Molecular, pubmed-meshheading:20214400-Protein Conformation, pubmed-meshheading:20214400-Protein Stability, pubmed-meshheading:20214400-Protein Structure, Tertiary, pubmed-meshheading:20214400-Rats, pubmed-meshheading:20214400-Receptors, Atrial Natriuretic Factor, pubmed-meshheading:20214400-Signal Transduction, pubmed-meshheading:20214400-Transcription Factors
pubmed:year
2010
pubmed:articleTitle
Role of juxtamembrane and transmembrane domains in the mechanism of natriuretic peptide receptor A activation.
pubmed:affiliation
Department of Pharmacology, Université de Montréal, Quebec, Canada H3T 1J4.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, Non-U.S. Gov't