Linked Life Data

20219842

Source:http://linkedlifedata.com/resource/pubmed/id/20219842

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
6
pubmed:dateCreated
2010-5-18
pubmed:abstractText
Exchanging each of the conserved aromatic residues of the NPxxY(x)(5,6)F sequence (at the boundary of helices 7 and 8) generated variants of the A(1) adenosine receptor that were retained within the cell. The mutations disconnected a link between alpha-helix 7 and cytosolic helix 8, likely destabilizing the structure of the proximal carboxyl terminus. The mutant receptors were rescued by incubation of cells with a pharmacochaperone, a membrane-permeable ligand that homosterically binds to the receptor; pharmacochaperoning restored the density of functional receptors at the plasma membrane. The following observations support the assumption that retention and the site of pharmacochaperone action were within bounds of the endoplasmic reticulum (ER): 1) the retained receptor colocalized with an ER marker; 2) pharmacochaperoning initiated receptor transfer to Golgi stacks; and 3) the inhibitor of glycoprotein synthesis tunicamycin suppressed receptor chaperoning. Our data are consistent with the hypothesis that pharmacochaperoning stabilizes the structure of late folding intermediates and lifts a block on maturation, allowing the receptors to exit from the ER. We suggest that the ER-associated 40-kDa heat shock protein family member D(1) receptor interacting protein 78 (DRiP78; M(r), approximately 78,000) represents a model executor of quality control. Overexpressed DRiP78 interacted physically with the A(1) receptor, inhibited export to the plasma membrane, and in this action was selective for the mutants relative to the wild-type receptor. Both agonist and antagonist were effective chaperone ligands. Thus, occupancy of the binding pocket corrected the mutation-induced disorder, indicating a mutual impingement of the transmembrane domain and the proximal carboxyl terminus in establishing the stable receptor fold.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
1521-0111
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
77
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
940-52
pubmed:meshHeading
pubmed:year
2010
pubmed:articleTitle
Pharmacochaperoning of the A1 adenosine receptor is contingent on the endoplasmic reticulum.
pubmed:affiliation
Institute of Pharmacology, Medizinische Universitädat Wien, Wädahringer Strasse 13A, 1090 Wien, Austria.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't