A Zinc Linchpin Motif in the MUTYH Glycosylase Interdomain Connector Is Required for Efficient Repair of DNA Damage

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• 作者：Lisa M. Engstrom ; Megan K. Brinkmeyer ; Yang Ha ; Alan G. Raetz ; Britt Hedman ; Keith O. Hodgson ; Edward I. Solomon ; Sheila S. David
• 刊名：Journal of the American Chemical Society
• 出版年：2014
• 出版时间：June 4, 2014
• 年：2014
• 卷：136
• 期：22
• 页码：7829-7832
• 全文大小：241K
• 年卷期：v.136,no.22(June 4, 2014)
• ISSN：1520-5126

文摘

Mammalian MutY glycosylases have a unique architecture that features an interdomain connector (IDC) that joins the catalytic N-terminal domain and 8-oxoguanine (OG) recognition C-terminal domain. The IDC has been shown to be a hub for interactions with protein partners involved in coordinating downstream repair events and signaling apoptosis. Herein, a previously unidentified zinc ion and its coordination by three Cys residues of the IDC region of eukaryotic MutY organisms were characterized by mutagenesis, ICP-MS, and EXAFS. In vitro kinetics and cellular assays on WT and Cys to Ser mutants have revealed an important function for zinc coordination on overall protein stability, iron鈥搒ulfur cluster insertion, and ability to mediate DNA damage repair. We propose that this 鈥渮inc linchpin鈥?motif serves to structurally organize the IDC and coordinate the damage recognition and base excision functions of the C- and N-terminal domains.