School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, China.
Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA.
Subcell Biochem. 2024;104:485-501. doi: 10.1007/978-3-031-58843-3_18.
Valosin-containing protein (VCP), also known as p97, is an evolutionarily conserved AAA+ ATPase essential for cellular homeostasis. Cooperating with different sets of cofactors, VCP is involved in multiple cellular processes through either the ubiquitin-proteasome system (UPS) or the autophagy/lysosomal route. Pathogenic mutations frequently found at the interface between the NTD domain and D1 ATPase domain have been shown to cause malfunction of VCP, leading to degenerative disorders including the inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD), amyotrophic lateral sclerosis (ALS), and cancers. Therefore, VCP has been considered as a potential therapeutic target for neurodegeneration and cancer. Most of previous studies found VCP predominantly exists and functions as a hexamer, which unfolds and extracts ubiquitinated substrates from protein complexes for degradation. However, recent studies have characterized a new VCP dodecameric state and revealed a controlling mechanism of VCP oligomeric states mediated by the D2 domain nucleotide occupancy. Here, we summarize our recent knowledge on VCP oligomerization, regulation, and potential implications of VCP in cellular function and pathogenic progression.
包含缬氨酸的蛋白（VCP），也被称为 p97，是一种进化上保守的 AAA+ATP 酶，对于细胞内环境的稳定至关重要。VCP 通过与不同的辅助因子结合，参与多种细胞过程，包括通过泛素-蛋白酶体系统（UPS）或自噬/溶酶体途径。在 NTD 结构域和 D1 ATP 酶结构域之间的界面上经常发现的致病性突变，已经表明会导致 VCP 的功能障碍，导致退行性疾病，包括与骨 Paget 病和额颞叶痴呆（IBMPFD）、肌萎缩侧索硬化症（ALS）和癌症相关的包涵体肌病。因此，VCP 已被认为是神经退行性疾病和癌症的潜在治疗靶点。大多数先前的研究发现，VCP 主要以六聚体的形式存在并发挥作用，它从蛋白质复合物中展开并提取泛素化的底物进行降解。然而，最近的研究已经描述了一种新的 VCP 十二聚体状态，并揭示了由 D2 结构域核苷酸占据介导的 VCP 寡聚状态的控制机制。在这里，我们总结了我们最近对 VCP 寡聚化、调节以及 VCP 在细胞功能和致病进展中的潜在作用的了解。
