美国诺华生物医学研究所Daniel A. King等研究人员合作解析MRAS-SHOC2-PP1C磷酸酶复合物的结构。该研究于2022年7月13日在线发表于国际一流学术期刊《自然》。
Author: Hauseman, Zachary J., Fodor, Michelle, Dhembi, Anxhela, Viscomi, Jessica, Egli, David, Bleu, Melusine, Katz, Stephanie, Park, Eunyoung, Jang, Dong Man, Porter, Kathryn A., Meili, Fabian, Guo, Hongqiu, Kerr, Grainne, Moll, Sandra, Velez-Vega, Camilo, Beyer, Kim S., Galli, Giorgio G., Maira, Saveur-Michel, Stams, Travis, Clark, Kirk, Eck, Michael J., Tordella, Luca, Thoma, Claudio R., King, Daniel A.
Issue&Volume: 2022-07-13
Abstract: RAS-MAPK signaling is fundamental for cell proliferation and altered in most human cancers1-3. However, our mechanistic understanding of how RAS signals through RAF is still incomplete. While studies revealed snapshots for autoinhibited and active RAF–MEK1–14-3-3 complexes4, the intermediate steps leading to RAF activation remain unclear. The MRAS-SHOC2-PP1c holophosphatase de-phosphorylates RAF on Serine 259 resulting in 14-3-3 partial displacement and RAF-RAS association3,5,6. MRAS, SHOC2 and PP1C are mutated in Rasopathies, developmental syndromes caused by aberrant MAPK pathway activation6-14 and SHOC2 itself has emerged as potential target in RTK-RAS driven tumors15-18. Despite its importance, structural understanding of the SHOC2 holophosphatase is lacking. Here we reveal a 1.95 X-ray crystal structure of the MRAS-SHOC2-PP1C complex. SHOC2 bridges PP1C and MRAS via its concave surface and enables reciprocal interactions between all three subunits. Biophysical characterization indicates a cooperative assembly driven by the MRAS GTP-bound active state, an observation extendible to other RAS isoforms. Our findings support the concept of a RAS-driven and multi-molecular model for RAF activation in which individual RAS-GTP molecules recruit RAF-14-3-3 and SHOC2-PP1C to produce downstream pathway activation. Importantly, we find that Rasopathy and cancer mutations reside at protein-protein interfaces within the holophosphatase, resulting in enhancing affinities and function. Collectively our findings shed light on a fundamental mechanism of RAS biology and on mechanisms for clinically observed enhanced RAS-MAPK signaling, thus providing the structural basis for therapeutic interventions.
DOI: 10.1038/s41586-022-05086-1
Source: https://www.nature.com/articles/s41586-022-05086-1
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
