期刊
DNA REPAIR
卷 94, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.dnarep.2020.102899
关键词
DNA damage repair; ADP-ribosylation; MacroD1; ADPR; Crystal structure
资金
- National Natural Science Foundation of China [81672794, 31670812]
- Ministry of Education ChunHui Project [23]
- Foundation of Hebei Educational committee [ZD2020183]
- Natural Science Foundation of Hebei province [C2018201171]
- Hebei Province Foundation for Returned Overseas Chinese Scholars
- Westlake University
MacroD1 is an enzyme that hydrolyzes protein mono-ADP-ribosylation. However, the key catalytic residues of MacroD1 in these biochemical reactions remain elusive. Here, we present the crystal structure of MacroD1 in a complex with ADP-ribose (ADPR). The beta 5-alpha 10-loop functions as a switch loop to mediate substrate recognition and right orientation. The conserved Phe(272) in the beta 5-alpha 10-loop plays a crucial role in the orientation of ADPR distal ribose, and a conserved hydrogen-bond network contributes significantly to hold and orient the catalytic water12, which mediates ADPR hydrolysis. Moreover, we found that MacroD1 was recruited to the sites of DNA damage via recognition of ADP-ribosylation at DNA lesions. The MacroD1-mediated ADPR hydrolysis is essential for DNA damage repair. Taken together, our study provides structural and functional insights into the molecular mechanism of MacroD1-mediated ADPR hydrolysis and its role in DNA damage repair.
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