Crystal Structure Reveals the Full Ras-Raf Interface and Advances Mechanistic Understanding of Raf Activation.
| Title: | Crystal Structure Reveals the Full Ras-Raf Interface and Advances Mechanistic Understanding of Raf Activation. |
|---|---|
| Authors: | Cookis T; Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA.; Mattos C; Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA. |
| Source: | Biomolecules [Biomolecules] 2021 Jul 07; Vol. 11 (7). Date of Electronic Publication: 2021 Jul 07. |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. |
| Language: | English |
| Journal Info: | Publisher: MDPI Country of Publication: Switzerland NLM ID: 101596414 Publication Model: Electronic Cited Medium: Internet ISSN: 2218-273X (Electronic) Linking ISSN: 2218273X NLM ISO Abbreviation: Biomolecules Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Basel, Switzerland : MDPI, 2011- |
| MeSH Terms: | Molecular Dynamics Simulation*; Proto-Oncogene Proteins c-raf/*chemistry ; Proto-Oncogene Proteins p21(ras)/*chemistry; Crystallography, X-Ray ; Humans ; Protein Domains ; Protein Structure, Quaternary |
| Abstract: | Ras and Raf-kinase interact through the Ras-binding (RBD) and cysteine-rich domains (CRD) of Raf to signal through the mitogen-activated protein kinase pathway, yet the molecular mechanism leading to Raf activation has remained elusive. We present the 2.8 Å crystal structure of the HRas-CRaf-RBD_CRD complex showing the Ras-Raf interface as a continuous surface on Ras, as seen in the KRas-CRaf-RBD_CRD structure. In molecular dynamics simulations of a Ras dimer model formed through the α4-α5 interface, the CRD is dynamic and located between the two Ras protomers, poised for direct or allosteric modulation of functionally relevant regions of Ras and Raf. We propose a molecular model in which Ras binding is involved in the release of Raf autoinhibition while the Ras-Raf complex dimerizes to promote a platform for signal amplification, with Raf-CRD centrally located to impact regulation and function. |
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| Grant Information: | MCB-1517295 National Science Foundation |
| Contributed Indexing: | Keywords: HRas–CRaf-RBD_CRD crystal structure; MAPK; Raf; Raf cystein-rich domain (CRD); Ras; Ras dimerization; Ras–Raf-RBD_CRD dimer simulations; allosteric connections |
| Substance Nomenclature: | EC 2.7.11.1 (Proto-Oncogene Proteins c-raf); EC 2.7.11.1 (Raf1 protein, human); EC 3.6.5.2 (HRAS protein, human); EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras)) |
| Entry Date(s): | Date Created: 20210806 Date Completed: 20210921 Latest Revision: 20240402 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC8301913 |
| DOI: | 10.3390/biom11070996 |
| PMID: | 34356620 |
| Database: | MEDLINE |
Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.