Document Detail


Functional motifs in the (6-4) photolyase crystal structure make a comparative framework for DNA repair photolyases and clock cryptochromes.
MedLine Citation:
PMID:  19359474     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Homologous flavoproteins from the photolyase (PHR)/cryptochrome (CRY) family use the FAD cofactor in PHRs to catalyze DNA repair and in CRYs to tune the circadian clock and control development. To help address how PHR/CRY members achieve these diverse functions, we determined the crystallographic structure of Arabidopsis thaliana (6-4) PHR (UVR3), which is strikingly (>65%) similar in sequence to human circadian clock CRYs. The structure reveals a substrate-binding cavity specific for the UV-induced DNA lesion, (6-4) photoproduct, and cofactor binding sites different from those of bacterial PHRs and consistent with distinct mechanisms for activities and regulation. Mutational analyses were combined with this prototypic structure for the (6-4) PHR/clock CRY cluster to identify structural and functional motifs: phosphate-binding and Pro-Lys-Leu protrusion motifs constricting access to the substrate-binding cavity above FAD, sulfur loop near the external end of the Trp electron-transfer pathway, and previously undefined C-terminal helix. Our results provide a detailed, unified framework for investigations of (6-4) PHRs and the mammalian CRYs. Conservation of key residues and motifs controlling FAD access and activities suggests that regulation of FAD redox properties and radical stability is essential not only for (6-4) photoproduct DNA repair, but also for circadian clock-regulating CRY functions. The structural and functional results reported here elucidate archetypal relationships within this flavoprotein family and suggest how PHRs and CRYs use local residue and cofactor tuning, rather than larger structural modifications, to achieve their diverse functions encompassing DNA repair, plant growth and development, and circadian clock regulation.
Authors:
Kenichi Hitomi; Luciano DiTacchio; Andrew S Arvai; Junpei Yamamoto; Sang-Tae Kim; Takeshi Todo; John A Tainer; Shigenori Iwai; Satchidananda Panda; Elizabeth D Getzoff
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2009-04-09
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  106     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2009 Apr 
Date Detail:
Created Date:  2009-05-06     Completed Date:  2009-06-05     Revised Date:  2013-06-02    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  6962-7     Citation Subset:  IM    
Affiliation:
Graduate School of Engineering Science, Osaka University, Toyonaka, Osaka 560-8531, Japan.
Data Bank Information
Bank Name/Acc. No.:
PDB/3FY4
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Animals
Arabidopsis / enzymology*,  genetics
Arabidopsis Proteins
Binding Sites
Circadian Rhythm*
Conserved Sequence
Cryptochromes
Crystallography, X-Ray
DNA Repair / genetics*
DNA, Plant / genetics,  metabolism*
Deoxyribodipyrimidine Photo-Lyase / chemistry*,  genetics,  metabolism*
Flavoproteins / genetics,  metabolism*
Hydrophobic and Hydrophilic Interactions
Molecular Sequence Data
Phosphates / chemistry,  metabolism
Phosphorylation
Protein Structure, Tertiary
Sequence Alignment
Grant Support
ID/Acronym/Agency:
1R32GM082083-01/GM/NIGMS NIH HHS; EY016807/EY/NEI NIH HHS; GM046312/GM/NIGMS NIH HHS; GM37684/GM/NIGMS NIH HHS; R01 GM037684-19/GM/NIGMS NIH HHS; R01 GM037684-20/GM/NIGMS NIH HHS; R01 GM037684-21/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Arabidopsis Proteins; 0/CRY1 protein, Arabidopsis; 0/Cryptochromes; 0/DNA, Plant; 0/Flavoproteins; 0/Phosphates; EC 4.1.99.-/pyrimidine(6-4)pyrimidone photolyase; EC 4.1.99.3/Deoxyribodipyrimidine Photo-Lyase
Comments/Corrections

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