p97/VCP AAA+ATP酶的结构见解:适配器相互作用如何协调不同的细胞功能。

The Journal of Biological Chemistry Pub Date : 2023-11-01 Epub Date: 2023-08-22 DOI:10.1016/j.jbc.2023.105182
Julian R Braxton, Daniel R Southworth
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引用次数: 0

摘要

p97/缬氨酸蛋白是一种重要的真核生物AAA+ATP酶,具有多种功能,包括蛋白质稳态、膜重塑和染色质调节。p97功能失调会导致严重的神经退行性疾病,并与癌症相关,使该蛋白成为重要的治疗靶点。p97通过水解驱动的通过其中心孔的易位从大分子组装体中提取多肽底物。越来越多的证据表明,这种活性与“适配器”伴侣蛋白高度协调,其中30多种已被鉴定,通常被描述为通过底物募集或修饰促进易位。在这样做的过程中,这些适配器实现了关键的p97依赖性功能,例如从内质网或线粒体提取错误折叠的蛋白质,并且可能是p97相对于其他AAA+转座酶具有极端功能多样性的原因。在这里,我们回顾了适配器蛋白的已知功能,并强调了最近的结构和生物化学进展,这些进展已经开始揭示适配器介导的p97功能调节的不同分子基础。这些研究表明,控制p97活性的机制范围远未得到充分探索,在理解最已知的适配器对p97的调节方面可能取得重大进展。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Structural insights of the p97/VCP AAA+ ATPase: How adapter interactions coordinate diverse cellular functionality.

p97/valosin-containing protein is an essential eukaryotic AAA+ ATPase with diverse functions including protein homeostasis, membrane remodeling, and chromatin regulation. Dysregulation of p97 function causes severe neurodegenerative disease and is associated with cancer, making this protein a significant therapeutic target. p97 extracts polypeptide substrates from macromolecular assemblies by hydrolysis-driven translocation through its central pore. Growing evidence indicates that this activity is highly coordinated by "adapter" partner proteins, of which more than 30 have been identified and are commonly described to facilitate translocation through substrate recruitment or modification. In so doing, these adapters enable critical p97-dependent functions such as extraction of misfolded proteins from the endoplasmic reticulum or mitochondria, and are likely the reason for the extreme functional diversity of p97 relative to other AAA+ translocases. Here, we review the known functions of adapter proteins and highlight recent structural and biochemical advances that have begun to reveal the diverse molecular bases for adapter-mediated regulation of p97 function. These studies suggest that the range of mechanisms by which p97 activity is controlled is vastly underexplored with significant advances possible for understanding p97 regulation by the most known adapters.

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