Structure of the SHOC2-MRAS-PP1C complex provides insights into RAF activation and Noonan syndrome.
Structure of the SHOC2-MRAS-PP1C complex provides insights into RAF activation and Noonan syndrome.
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DOI：
10.1038/s41594-022-00841-4
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发表时间：
2022-10
影响因子：
16.8
通讯作者：
Simanshu, Dhirendra K.
中科院分区：
文献类型：
--
作者：
Bonsor, Daniel A.;Alexander, Patrick;Snead, Kelly;Hartig, Nicole;Drew, Matthew;Messing, Simon;Finci, Lorenzo, I;Nissley, Dwight, V;McCormick, Frank;Esposito, Dominic;Rodriguez-Viciana, Pablo;Stephen, Andrew G.;Simanshu, Dhirendra K.
SHOC 2在多种KRAS癌细胞系中作为与MEK抑制剂的强合成致死相互作用物。SHOC 2与MRAS和PP 1C形成异源三聚体复合物，其通过使RAF激酶上的特定磷酸丝氨酸去磷酸化而对调节RAF和MAPK途径活化至关重要。在这里，我们展示了SHOC 2-MRAS-PP 1C（SMP）复合物和apo-SHOC 2的高分辨率晶体结构。我们的结构表明，SHOC 2，MRAS和PP 1C形成一个稳定的三元复合物，其中所有三种蛋白质协同相互作用。我们的研究结果表明，PP 1C的RAF底物的去磷酸化增强后，与SHOC 2和MRAS相互作用。SMP复合物仅在MRAS处于活性状态时形成，并且依赖于SHOC 2通过将PP 1C和MRAS结合在一起而在复合物中充当支架蛋白。我们的研究结果为SMP复合物在RAF激活中的作用以及努南综合征中发现的突变如何增强复合物的形成提供了结构性见解，并揭示了治疗干预的新途径。
SHOC2 acts as a strong synthetic lethal interactor with MEK inhibitors in multiple KRAS cancer cell lines. SHOC2 forms a heterotrimeric complex with MRAS and PP1C that is essential for regulating RAF and MAPK-pathway activation by dephosphorylating a specific phosphoserine on RAF kinases. Here we present the high-resolution crystal structure of the SHOC2–MRAS–PP1C (SMP) complex and apo-SHOC2. Our structures reveal that SHOC2, MRAS, and PP1C form a stable ternary complex in which all three proteins synergistically interact with each other. Our results show that dephosphorylation of RAF substrates by PP1C is enhanced upon interacting with SHOC2 and MRAS. The SMP complex forms only when MRAS is in an active state and is dependent on SHOC2 functioning as a scaffolding protein in the complex by bringing PP1C and MRAS together. Our results provide structural insights into the role of the SMP complex in RAF activation and how mutations found in Noonan syndrome enhance complex formation, and reveal new avenues for therapeutic interventions.
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影响因子：
30.8
作者：
Cordeddu, Viviana;Di Schiavi, Elia;Pennacchio, Len A.;Ma'ayan, Avi;Sarkozy, Anna;Fodale, Valentina;Cecchetti, Serena;Cardinale, Alessio;Martin, Joel;Schackwitz, Wendy;Lipzen, Anna;Zampino, Giuseppe;Mazzanti, Laura;Digilio, Maria C.;Martinelli, Simone;Flex, Elisabetta;Lepri, Francesca;Bartholdi, Deborah;Kutsche, Kerstin;Ferrero, Giovanni B.;Anichini, Cecilia;Selicorni, Angelo;Rossi, Cesare;Tenconi, Romano;Zenker, Martin;Merlo, Daniela;Dallapiccola, Bruno;Iyengar, Ravi;Bazzicalupo, Paolo;Gelb, Bruce D.;Tartaglia, Marco
通讯作者：
Tartaglia, Marco
影响因子：
16.6
作者：
Martinez Fiesco JA;Durrant DE;Morrison DK;Zhang P
通讯作者：
Zhang P
影响因子：
4.8
作者：
Hurley, Thomas D.;Yang, Jie;DePaoli-Roach, Anna A.
通讯作者：
DePaoli-Roach, Anna A.
影响因子：
2
作者：
Huckstadt, Victoria;Chinton, Josefina;Gravina, Luis Pablo
通讯作者：
Gravina, Luis Pablo
影响因子：
64.8
作者：
GOLDBERG, J;HUANG, HB;KURIYAN, J
通讯作者：
KURIYAN, J