p97 Disease Mutations Modulate Nucleotide-Induced Conformation to Alter Protein-Protein Interactions.
p97 Disease Mutations Modulate Nucleotide-Induced Conformation to Alter Protein-Protein Interactions.
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DOI：
10.1021/acschembio.6b00350
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发表时间：
2016-08-19
影响因子：
4
通讯作者：
Arkin MR
中科院分区：
文献类型：
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作者：
Bulfer SL;Chou TF;Arkin MR
AAA+ ATP酶p97/VCP至少有三种构象，依赖于ADP和ATP的结合，并改变N-末端蛋白质-蛋白质相互作用（PPI）结构域的方向为“上”和“下”构象。在N结构域和D1-ATP酶结构域的界面发现了引起多系统蛋白质病1（MSP 1）的点突变，并可能改变p97的构象偏好。此外，“衔接子”蛋白与N结构域的结合调节p97的催化活性。我们建议，p97/适配器PPI耦合到p97构象状态。我们评估了核苷酸和接头蛋白p37和p47与野生型p97和MSP 1突变体的结合。值得注意的是，与ATP结合构象相比，p47和p37与野生型p97的ADP结合构象的结合弱8倍。然而，MSP 1突变体失去了这种核苷酸诱导的构象偶联，因为它们使N结构域的ADP结合的“向下”构象不稳定。与PPI偶联的构象损失可能有助于MSP 1的机制。
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.