Document Detail

Mechanisms of autoinhibition in cyclic nucleotide-dependent protein kinases.
MedLine Citation:
PMID:  11861209     Owner:  NLM     Status:  MEDLINE    
Cyclic AMP-dependent protein kinase (PKA) and cGMP-dependent protein kinase (PKG) are autoinhibited through multiple interactions between their respective regulatory and catalytic domains. A large portion of this autoinhibition occurs through interactions between residues within the catalytic domain and those within either a substrate-like sequence (-RRXSX-) or pseudosubstrate sequence (-RRXAX-) in the regulatory domains. These contacts effectively inhibit catalysis by blocking substrate binding. Particularly important contacts involve the P-2, P-3, and P+1 residues where either serine, which is potentially autophosphorylated, or alanine occupies the P0 position. The primary sequence is apparently less important for autoinhibition in PKGs than in PKAs, and a conserved serine at P+2 in PKGs is important for autoinhibitory contacts. Elements outside the substrate-related sequences also contribute to autoinhibition in both PKA and PKG. For example, synthetic peptides with relatively short pseudosubstrate sequences are weak inhibitors; while heat-denatured RII subunit does not inhibit catalytic subunit, it is still rapidly autophosphorylated; and truncated PKGs lacking the substrate-like sequence are still partially autoinhibited. Thus, capacity for autoinhibition of PKA or PKG is provided by contacts involving direct interactions with the catalytic site and by contacts that stabilize an inactive conformation.
Sharron H Francis; Celeste Poteet-Smith; Jennifer L Busch; Robyn Richie-Jannetta; Jackie D Corbin
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.; Review     Date:  2002-03-01
Journal Detail:
Title:  Frontiers in bioscience : a journal and virtual library     Volume:  7     ISSN:  1093-4715     ISO Abbreviation:  Front. Biosci.     Publication Date:  2002 Mar 
Date Detail:
Created Date:  2002-02-25     Completed Date:  2002-04-19     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  9709506     Medline TA:  Front Biosci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  d580-92     Citation Subset:  IM    
Dept. of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232-0615, USA.
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MeSH Terms
Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors*,  chemistry,  metabolism*,  physiology
Cyclic GMP-Dependent Protein Kinases / antagonists & inhibitors*,  chemistry,  metabolism*,  physiology
Grant Support
Reg. No./Substance:
EC AMP-Dependent Protein Kinases; EC GMP-Dependent Protein Kinases

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