Document Detail

Receptor-mediated activation of Gsalpha: evidence for intramolecular signal transduction.
MedLine Citation:
PMID:  9614199     Owner:  NLM     Status:  MEDLINE    
To investigate the mechanism by which cell surface receptors activate heterotrimeric G proteins, we applied a scanning mutagenesis approach to the carboxyl-terminal 40% of alphas (residues 236-394) to identify residues that play a role in receptor-mediated activation. We identified four regions of sequence in which mutations significantly impaired receptor-dependent stimulation of cAMP synthesis in transiently transfected cyc- S49 lymphoma cells, which lack endogenous alphas. Residues at the carboxyl terminus are likely to be receptor contact sites. Buried residues near the bound GDP are connected to the carboxyl terminus by an alpha helix and may regulate GDP affinity. Residues in two adjacent loops of the GTPase domain at the interface with the helical domain, one of which includes a region, switch III, that changes conformation on GTP binding, are positioned to relay the receptor-initiated signal across the domain interface to facilitate GDP release. Consistent with this hypothesis, replacing the helical domain of alphas with that of alphai2 in an alphas/alphai2/alphas chimera corrects the defect in receptor-mediated activation caused by alphai2 substitutions on the GTPase side of the interface. Thus, complementary interactions between residues across the domain interface seem to play a role in receptor-catalyzed activation.
S R Marsh; G Grishina; P T Wilson; C H Berlot
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Molecular pharmacology     Volume:  53     ISSN:  0026-895X     ISO Abbreviation:  Mol. Pharmacol.     Publication Date:  1998 Jun 
Date Detail:
Created Date:  1998-06-25     Completed Date:  1998-06-25     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0035623     Medline TA:  Mol Pharmacol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  981-90     Citation Subset:  IM    
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520-8026, USA.
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MeSH Terms
Amino Acid Sequence
Cyclic AMP / metabolism
GTP Phosphohydrolases / chemistry
GTP-Binding Proteins / chemistry,  physiology*
Molecular Sequence Data
Protein Structure, Secondary
Receptors, Cell Surface / physiology*
Signal Transduction*
Structure-Activity Relationship
Grant Support
Reg. No./Substance:
0/Receptors, Cell Surface; 60-92-4/Cyclic AMP; EC 3.6.1.-/GTP Phosphohydrolases; EC 3.6.1.-/GTP-Binding Proteins

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