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研究揭示SHOC2调控RAS信号的结构基础
2022-06-30 19:49
来源：小柯机器人

2022年6月29日，《自然》杂志在线发表了美国基因泰克公司Jawahar Sudhamsu、Sarah G. Hymowitz等研究人员的合作成果。该研究揭示SHOC2调控RAS信号的结构基础。

据研究人员介绍，RAS-RAF途径是人类癌症中最常见的失调途径之一。尽管经过几十年的研究，对激酶RAF的二聚体化和激活的分子机制的理解仍然有限。最近与14-3-3结合的非活性RAF单体和活性RAF二聚体的结构揭示了14-3-3通过特定的磷丝氨酸残基稳定两种RAF构象的机制。在RAF二聚体化之前，蛋白磷酸酶1催化亚基（PP1C）必须使RAF的N端磷酸丝氨酸（NTpS）去磷酸化，从而解除14-3-3的抑制，尽管PP1C孤立地缺乏内在的底物选择性。SHOC2是一个重要的支架蛋白，它与PP1C和RAS一起参与RAF NTpS11的去磷酸化，但SHOC2的结构和推定的SHOC2-PP1C-RAS复合物的结构仍然未知。
 
研究人员报道了SHOC2-PP1C-MRAS复合物的冷冻电镜结构，整体分辨率为3埃，从而揭示了一个三方分子结构，其中新月形的SHOC2作为一个摇篮，将PP1C和MRAS聚集在一起。这项工作证明了多种RAS异构体对复合物形成的GTP依赖性，划定了RAS异构体对复合物组装的偏好，并揭示了SHOC2支架和RAS如何共同驱动PP1C对RAF NTpS的特异性。数据表明，与疾病相关的突变会影响复合物的组装，从而揭示了两种RAS分子对RAF激活的同时要求，并为发现针对这一途径的新类抑制剂建立了合理的途径。
 
附：英文原文
 
Title: Structural basis for SHOC2 modulation of RAS signalling

Author: Liau, Nicholas P. D., Johnson, Matthew C., Izadi, Saeed, Gerosa, Luca, Hammel, Michal, Bruning, John M., Wendorff, Timothy J., Phung, Wilson, Hymowitz, Sarah G., Sudhamsu, Jawahar

Issue&Volume: 2022-06-29

Abstract: The RAS–RAF pathway is one of the most commonly dysregulated in human cancers1,2,3. Despite decades of study, understanding of the molecular mechanisms underlying dimerization and activation4 of the kinase RAF remains limited. Recent structures of inactive RAF monomer5 and active RAF dimer5,6,7,8 bound to 14-3-39,10 have revealed the mechanisms by which 14-3-3 stabilizes both RAF conformations via specific phosphoserine residues. Prior to RAF dimerization, the protein phosphatase 1 catalytic subunit (PP1C) must dephosphorylate the N-terminal phosphoserine (NTpS) of RAF11 to relieve inhibition by 14-3-3, although PP1C in isolation lacks intrinsic substrate selectivity. SHOC2 is as an essential scaffolding protein that engages both PP1C and RAS to dephosphorylate RAF NTpS11,12,13, but the structure of SHOC2 and the architecture of the presumptive SHOC2–PP1C–RAS complex remain unknown. Here we present a cryo-electron microscopy structure of the SHOC2–PP1C–MRAS complex to an overall resolution of 3, revealing a tripartite molecular architecture in which a crescent-shaped SHOC2 acts as a cradle and brings together PP1C and MRAS. Our work demonstrates the GTP dependence of multiple RAS isoforms for complex formation, delineates the RAS-isoform preference for complex assembly, and uncovers how the SHOC2 scaffold and RAS collectively drive specificity of PP1C for RAF NTpS. Our data indicate that disease-relevant mutations affect complex assembly, reveal the simultaneous requirement of two RAS molecules for RAF activation, and establish rational avenues for discovery of new classes of inhibitors to target this pathway.

DOI: 10.1038/s41586-022-04838-3

Source: https://www.nature.com/articles/s41586-022-04838-3

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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