Document Detail


Structural basis for autoinhibition and mutational activation of eukaryotic initiation factor 2alpha protein kinase GCN2.
MedLine Citation:
PMID:  15964839     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The GCN2 protein kinase coordinates protein synthesis with levels of amino acid stores by phosphorylating eukaryotic translation initiation factor 2. The autoinhibited form of GCN2 is activated in cells starved of amino acids by binding of uncharged tRNA to a histidyl-tRNA synthetase-like domain. Replacement of Arg-794 with Gly in the PK domain (R794G) activates GCN2 independently of tRNA binding. Crystal structures of the GCN2 protein kinase domain have been determined for wild-type and R794G mutant forms in the apo state and bound to ATP/AMPPNP. These structures reveal that GCN2 autoinhibition results from stabilization of a closed conformation that restricts ATP binding. The R794G mutant shows increased flexibility in the hinge region connecting the N- and C-lobes, resulting from loss of multiple interactions involving Arg794. This conformational change is associated with intradomain movement that enhances ATP binding and hydrolysis. We propose that intramolecular interactions following tRNA binding remodel the hinge region in a manner similar to the mechanism of enzyme activation elicited by the R794G mutation.
Authors:
Anil K Padyana; Hongfang Qiu; Antonina Roll-Mecak; Alan G Hinnebusch; Stephen K Burley
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.     Date:  2005-06-17
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  280     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2005 Aug 
Date Detail:
Created Date:  2005-08-08     Completed Date:  2005-09-22     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  29289-99     Citation Subset:  IM    
Affiliation:
Structural GenomiX, Inc., San Diego, CA 92121, USA.
Data Bank Information
Bank Name/Acc. No.:
PDB/1ZY4;  1ZY5;  1ZYC
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MeSH Terms
Descriptor/Qualifier:
Adenosine Triphosphate / chemistry
Amino Acid Sequence
Arginine / chemistry
Binding Sites
Crystallography, X-Ray
Dimerization
Escherichia coli / metabolism
Histidine / chemistry
Hydrolysis
Magnesium / chemistry
Models, Molecular
Molecular Sequence Data
Mutation
Phosphorylation
Protein Binding
Protein Conformation
Protein Kinases / chemistry*
Protein Structure, Tertiary
Protein-Serine-Threonine Kinases
RNA, Transfer / chemistry
Saccharomyces cerevisiae / metabolism
Saccharomyces cerevisiae Proteins
Sequence Homology, Amino Acid
eIF-2 Kinase / metabolism*
Grant Support
ID/Acronym/Agency:
R01 GM061262-05/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Saccharomyces cerevisiae Proteins; 56-65-5/Adenosine Triphosphate; 71-00-1/Histidine; 74-79-3/Arginine; 7439-95-4/Magnesium; 9014-25-9/RNA, Transfer; EC 2.7.-/Protein Kinases; EC 2.7.11.1/GCN2 protein, S cerevisiae; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/eIF-2 Kinase

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