The AAA+-type ATPase p97 governs an ever-expanding number of cellular processes reaching from degradation of damaged proteins and organelles to key signaling events and chromatin regulation with thousands of client proteins. With its relevance for cellular homeostasis and genome stability, it is linked to muscular and neuronal degeneration and, conversely, constitutes an attractive anti-cancer drug target. Its molecular function is ATP-driven protein unfolding, which is directed by ubiquitin and assisted by a host of cofactor proteins. This activity underlies p97’s diverse ability to pull proteins out of membranes, unfold proteins for proteasomal degradation, or segregate proteins from partners for downstream activity. Recent advances in structural analysis and biochemical reconstitution have underscored this notion, resolved detailed molecular motions within the p97 hexamer, and suggested substrate threading through the central channel of the p97 hexamer as the driving mechanism. We will discuss the mechanisms and open questions in the context of the diverse cellular activities.

AAA +型ATPase p97控制着不断增长的细胞过程，从受损的蛋白质和细胞器的降解到关键的信号事件和数千种客户蛋白质的染色质调节。由于它与细胞动态平衡和基因组稳定性有关，因此它与肌肉和神经元变性有关，并且相反，它构成了有吸引力的抗癌药物靶标。它的分子功能是ATP驱动的蛋白解折叠，这是由泛素指导的，并辅以许多辅因子蛋白。这种活性是p97从膜中抽出蛋白质，展开蛋白质以进行蛋白酶体降解或从伴侣中分离蛋白质以进行下游活性的多种能力的基础。结构分析和生化重组的最新进展突显了这一概念，解决了p97六聚体内部的详细分子运动，并建议将底物穿过p97六聚体的中心通道作为驱动机制。我们将在各种细胞活动的背景下讨论机制和未解决的问题。