Next Article in Journal
Function of Dental Follicle Progenitor/Stem Cells and Their Potential in Regenerative Medicine: From Mechanisms to Applications
Next Article in Special Issue
Lipid Profiles of RAS Nanoclusters Regulate RAS Function
Previous Article in Journal
Phosphorylation of RCC1 on Serine 11 Facilitates G1/S Transition in HPV E7-Expressing Cells
Previous Article in Special Issue
Spotlight on Accessory Proteins: RTK-RAS-MAPK Modulators as New Therapeutic Targets
Article

Crystal Structure Reveals the Full Ras–Raf Interface and Advances Mechanistic Understanding of Raf Activation

Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Daniel Abankwa
Biomolecules 2021, 11(7), 996; https://doi.org/10.3390/biom11070996
Received: 7 May 2021 / Revised: 1 July 2021 / Accepted: 2 July 2021 / Published: 7 July 2021
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. View Full-Text
Keywords: Ras; Raf; Raf cystein-rich domain (CRD); Ras dimerization; HRas–CRaf-RBD_CRD crystal structure; Ras–Raf-RBD_CRD dimer simulations; allosteric connections; MAPK Ras; Raf; Raf cystein-rich domain (CRD); Ras dimerization; HRas–CRaf-RBD_CRD crystal structure; Ras–Raf-RBD_CRD dimer simulations; allosteric connections; MAPK
Show Figures

Graphical abstract

MDPI and ACS Style

Cookis, T.; Mattos, C. Crystal Structure Reveals the Full Ras–Raf Interface and Advances Mechanistic Understanding of Raf Activation. Biomolecules 2021, 11, 996. https://doi.org/10.3390/biom11070996

AMA Style

Cookis T, Mattos C. Crystal Structure Reveals the Full Ras–Raf Interface and Advances Mechanistic Understanding of Raf Activation. Biomolecules. 2021; 11(7):996. https://doi.org/10.3390/biom11070996

Chicago/Turabian Style

Cookis, Trinity, and Carla Mattos. 2021. "Crystal Structure Reveals the Full Ras–Raf Interface and Advances Mechanistic Understanding of Raf Activation" Biomolecules 11, no. 7: 996. https://doi.org/10.3390/biom11070996

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop