دورية أكاديمية
Structure-function analysis of the SHOC2-MRAS-PP1C holophosphatase complex.
| العنوان: | Structure-function analysis of the SHOC2-MRAS-PP1C holophosphatase complex. |
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| المؤلفون: | Kwon JJ; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Harvard Medical School, Boston, Massachusetts, USA., Hajian B; Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Bian Y; Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Young LC; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA., Amor AJ; Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Fuller JR; Helix Biostructures, Indianapolis, IN, USA., Fraley CV; Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Sykes AM; Harvard Medical School, Boston, Massachusetts, USA.; Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA, USA., So J; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Harvard Medical School, Boston, Massachusetts, USA., Pan J; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Harvard Medical School, Boston, Massachusetts, USA., Baker L; Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Lee SJ; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Harvard Medical School, Boston, Massachusetts, USA., Wheeler DB; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Mayhew DL; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Harvard Medical School, Boston, Massachusetts, USA., Persky NS; Genetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Yang X; Genetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Root DE; Genetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Barsotti AM; Deerfield Discovery and Development, Deerfield Management, New York, NY, USA., Stamford AW; Deerfield Discovery and Development, Deerfield Management, New York, NY, USA., Perry CK; Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Burgin A; Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA, USA., McCormick F; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.; NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD, USA., Lemke CT; Center for the Development of Therapeutics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. clemke@broadinstitute.org., Hahn WC; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA. william_hahn@dfci.harvard.edu.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. william_hahn@dfci.harvard.edu.; Harvard Medical School, Boston, Massachusetts, USA. william_hahn@dfci.harvard.edu.; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. william_hahn@dfci.harvard.edu., Aguirre AJ; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA. andrew_aguirre@dfci.harvard.edu.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. andrew_aguirre@dfci.harvard.edu.; Harvard Medical School, Boston, Massachusetts, USA. andrew_aguirre@dfci.harvard.edu.; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. andrew_aguirre@dfci.harvard.edu. |
| المصدر: | Nature [Nature] 2022 Sep; Vol. 609 (7926), pp. 408-415. Date of Electronic Publication: 2022 Jul 13. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Nature Publishing Group Country of Publication: England NLM ID: 0410462 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-4687 (Electronic) Linking ISSN: 00280836 NLM ISO Abbreviation: Nature Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Basingstoke : Nature Publishing Group Original Publication: London, Macmillan Journals ltd. |
| مواضيع طبية MeSH: | Cryoelectron Microscopy* , Intracellular Signaling Peptides and Proteins*/chemistry , Intracellular Signaling Peptides and Proteins*/genetics , Intracellular Signaling Peptides and Proteins*/metabolism , Multiprotein Complexes*/chemistry , Multiprotein Complexes*/metabolism , Multiprotein Complexes*/ultrastructure , Protein Phosphatase 1*/chemistry , Protein Phosphatase 1*/metabolism , Protein Phosphatase 1*/ultrastructure , ras Proteins*/chemistry , ras Proteins*/metabolism , ras Proteins*/ultrastructure, Amino Acid Motifs ; Binding Sites ; Guanosine Triphosphate/metabolism ; Humans ; MAP Kinase Signaling System ; Mutation, Missense ; Phosphorylation ; Protein Binding ; Protein Stability ; raf Kinases |
| مستخلص: | 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 signalling 1 . SHOC2 forms a ternary complex with MRAS and PP1C, and human germline gain-of-function mutations in this complex result in congenital RASopathy syndromes 2-5 . 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 . (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.) |
| التعليقات: | Comment in: Nature. 2022 Sep;609(7926):248-249. (PMID: 35970881) |
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| معلومات مُعتمدة: | R35 CA197709 United States CA NCI NIH HHS; K08 CA218420 United States CA NCI NIH HHS; U01 CA176058 United States CA NCI NIH HHS; F32 CA243290 United States CA NCI NIH HHS; U01 CA250549 United States CA NCI NIH HHS; P50 CA127003 United States CA NCI NIH HHS; P01 CA203655 United States CA NCI NIH HHS; U01 CA224146 United States CA NCI NIH HHS |
| المشرفين على المادة: | 0 (Intracellular Signaling Peptides and Proteins) 0 (MRAS protein, human) 0 (Multiprotein Complexes) 0 (SHOC2 protein, human) 86-01-1 (Guanosine Triphosphate) EC 2.7.11.1 (raf Kinases) EC 3.1.3.16 (Protein Phosphatase 1) EC 3.6.5.2 (ras Proteins) |
| تواريخ الأحداث: | Date Created: 20220713 Date Completed: 20220909 Latest Revision: 20231230 |
| رمز التحديث: | 20231231 |
| مُعرف محوري في PubMed: | PMC9694338 |
| DOI: | 10.1038/s41586-022-04928-2 |
| PMID: | 35831509 |
| قاعدة البيانات: | MEDLINE |
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Full Text Finder | تدمد: | 1476-4687 |
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| DOI: | 10.1038/s41586-022-04928-2 |