小柯机器人

科学家完成SHOC2-MRAS-PP1C磷酸酶复合物的结构-功能分析
2022-07-17 16:40
来源：小柯机器人

美国哈佛医学院Andrew J. Aguirre等研究人员合作完成SHOC2-MRAS-PP1C磷酸酶复合物的结构-功能分析。2022年7月13日，国际知名学术期刊《自然》在线发表了这一成果。

据研究人员介绍，受体酪氨酸激酶（RTK）-RAS信号通过下游的丝裂原活化蛋白激酶（MAPK）级联调节细胞的增殖和生存。SHOC2-MRAS-PP1C磷酸酶复合物作为RTK-RAS信号的关键调节器，通过消除RAF家族蛋白上的抑制性磷酸化事件来增强MAPK信号的作用。SHOC2与MRAS和PP1C形成三元复合物，该复合物的人类种系功能获得性突变导致了先天性RAS病综合征。然而，人们对这一复合体的结构和组装知之甚少。
 
研究人员使用冷冻电镜来解析了SHOC2-MRAS-PP1C复合物的结构。研究人员定义了能酶相互作用的生物物理学原理，阐明了该复合物的组装顺序，并通过深度突变扫描系统地研究了SHOC2几乎所有可能错义变体的功能后果。结果表明，SHOC2通过富含亮氨酸重复区的凹面与PP1C和MRAS结合，并通过含有隐性RVXF模体的N端无序区进一步与PP1C结合。复合物的形成最初是由SHOC2和PP1C之间的相互作用介导的，并通过加载GTP的MRAS的结合而稳定。这些观察结果解释了RAS病和癌症中SHOC2的突变版本如何稳定复合物成员的相互作用来增强磷酸酶的活性。
 
总之，这个综合的结构-功能模型全面地定义了SHOC2-MRAS-PP1C磷酸酶复合物中的关键结合作用，并将为治疗的发展提供信息。
 
附：英文原文
 
Title: Structure–function analysis of the SHOC2–MRAS–PP1C holophosphatase complex

Author: Kwon, Jason J., Hajian, Behnoush, Bian, Yuemin, Young, Lucy C., Amor, Alvaro J., Fuller, James R., Fraley, Cara V., Sykes, Abbey M., So, Jonathan, Pan, Joshua, Baker, Laura, Lee, Sun Joo, Wheeler, Douglas B., Mayhew, David L., Persky, Nicole S., Yang, Xiaoping, Root, David E., Barsotti, Anthony M., Stamford, Andrew W., Perry, Charles K., Burgin, Alex, McCormick, Frank, Lemke, Christopher T., Hahn, William C., Aguirre, Andrew J.

Issue&Volume: 2022-07-13

Abstract: Receptor tyrosine kinase (RTK)–RAS signalling through the downstream mitogen-activated protein kinase (MAPK) cascade regulates cell proliferation and survival. The SHOC2–MRAS–PP1C holophosphatase complex functions as a key regulator of RTK–RAS signalling by removing an inhibitory phosphorylation event on the RAF family of proteins to potentiate MAPK signalling1. SHOC2 forms a ternary complex with MRAS and PP1C, and human germline gain-of-function mutations in this complex result in congenital RASopathy syndromes2,3,4,5. However, the structure and assembly of this complex are poorly understood. Here we use cryo-electron microscopy to resolve the structure of the SHOC2–MRAS–PP1C complex. We define the biophysical principles of holoenzyme interactions, elucidate the assembly order of the complex, and systematically interrogate the functional consequence of nearly all of the possible missense variants of SHOC2 through deep mutational scanning. We show that SHOC2 binds PP1C and MRAS through the concave surface of the leucine-rich repeat region and further engages PP1C through the N-terminal disordered region that contains a cryptic RVXF motif. Complex formation is initially mediated by interactions between SHOC2 and PP1C and is stabilized by the binding of GTP-loaded MRAS. These observations explain how mutant versions of SHOC2 in RASopathies and cancer stabilize the interactions of complex members to enhance holophosphatase activity. Together, this integrative structure–function model comprehensively defines key binding interactions within the SHOC2–MRAS–PP1C holophosphatase complex and will inform therapeutic development .

DOI: 10.1038/s41586-022-04928-2

Source: https://www.nature.com/articles/s41586-022-04928-2

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html


本期文章：《自然》：Online/在线发表

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