p97 Disease Mutations Modulate Nucleotide-Induced Conformation to Alter Protein–Protein Interactions

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• 作者：Stacie L. Bulfer ; Tsui-Fen Chou ; Michelle R. Arkin
• 刊名：ACS Chemical Biology
• 出版年：2016
• 出版时间：August 19, 2016
• 年：2016
• 卷：11
• 期：8
• 页码：2112-2116
• 全文大小：377K
• 年卷期：0
• ISSN：1554-8937

文摘

The AAA+ ATPase p97/VCP adopts at least three conformations that depend on the binding of ADP and ATP and alter the orientation of the N-terminal protein–protein interaction (PPI) domain into “up” and “down” conformations. Point mutations that cause multisystem proteinopathy 1 (MSP1) are found at the interface of the N domain and D1-ATPase domain and potentially alter the conformational preferences of p97. Additionally, binding of “adaptor” proteins to the N-domain regulates p97’s catalytic activity. We propose that p97/adaptor PPIs are coupled to p97 conformational states. We evaluated the binding of nucleotides and the adaptor proteins p37 and p47 to wild-type p97 and MSP1 mutants. Notably, p47 and p37 bind 8-fold more weakly to the ADP-bound conformation of wild-type p97 compared to the ATP-bound conformation. However, MSP1 mutants lose this nucleotide-induced conformational coupling because they destabilize the ADP-bound, “down” conformation of the N-domain. Loss in conformation coupling to PPIs could contribute to the mechanism of MSP1.