Publication Date:
2012-05-15
Description:
Poly(ADP-ribose) polymerase-1 (PARP-1) (ADP, adenosine diphosphate) has a modular domain architecture that couples DNA damage detection to poly(ADP-ribosyl)ation activity through a poorly understood mechanism. Here, we report the crystal structure of a DNA double-strand break in complex with human PARP-1 domains essential for activation (Zn1, Zn3, WGR-CAT). PARP-1 engages DNA as a monomer, and the interaction with DNA damage organizes PARP-1 domains into a collapsed conformation that can explain the strong preference for automodification. The Zn1, Zn3, and WGR domains collectively bind to DNA, forming a network of interdomain contacts that links the DNA damage interface to the catalytic domain (CAT). The DNA damage-induced conformation of PARP-1 results in structural distortions that destabilize the CAT. Our results suggest that an increase in CAT protein dynamics underlies the DNA-dependent activation mechanism of PARP-1.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3532513/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3532513/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Langelier, Marie-France -- Planck, Jamie L -- Roy, Swati -- Pascal, John M -- P30 EB009998/EB/NIBIB NIH HHS/ -- P30CA56036/CA/NCI NIH HHS/ -- R01 GM087282/GM/NIGMS NIH HHS/ -- R01087282/PHS HHS/ -- New York, N.Y. -- Science. 2012 May 11;336(6082):728-32. doi: 10.1126/science.1216338.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Molecular Biology, The Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22582261" target="_blank"〉PubMed〈/a〉
Keywords:
Catalytic Domain
;
Crystallography, X-Ray
;
DNA/*chemistry/*metabolism
;
*DNA Breaks, Double-Stranded
;
Enzyme Stability
;
Humans
;
Hydrophobic and Hydrophilic Interactions
;
Models, Molecular
;
Nucleic Acid Conformation
;
Poly Adenosine Diphosphate Ribose/*metabolism
;
Poly(ADP-ribose) Polymerases/*chemistry/*metabolism
;
Protein Binding
;
Protein Conformation
;
Protein Structure, Tertiary
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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