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Mechanisms of Ras Membrane Organization and Signaling: Ras Rocks Again

1
Cancer Cell Biology and Drug Discovery Group, Department of Life Sciences and Medicine, University of Luxembourg, Esch-sur-Alzette 4362, Luxembourg
2
Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, 6431 Fannin St., Houston, TX 77030, USA
*
Authors to whom correspondence should be addressed.
Biomolecules 2020, 10(11), 1522; https://doi.org/10.3390/biom10111522
Received: 13 October 2020 / Revised: 3 November 2020 / Accepted: 4 November 2020 / Published: 6 November 2020
Ras is the most frequently mutated oncogene and recent drug development efforts have spurred significant new research interest. Here we review progress toward understanding how Ras functions in nanoscale, proteo-lipid signaling complexes on the plasma membrane, called nanoclusters. We discuss how G-domain reorientation is plausibly linked to Ras-nanoclustering and -dimerization. We then look at how these mechanistic features could cooperate in the engagement and activation of RAF by Ras. Moreover, we show how this structural information can be integrated with microscopy data that provide nanoscale resolution in cell biological experiments. Synthesizing the available data, we propose to distinguish between two types of Ras nanoclusters, an active, immobile RAF-dependent type and an inactive/neutral membrane anchor-dependent. We conclude that it is possible that Ras reorientation enables dynamic Ras dimerization while the whole Ras/RAF complex transits into an active state. These transient di/oligomer interfaces of Ras may be amenable to pharmacological intervention. We close by highlighting a number of open questions including whether all effectors form active nanoclusters and whether there is an isoform specific composition of Ras nanocluster. View Full-Text
Keywords: Ras; nanocluster; Raf; dimerization; Ras orientation; membrane; HVR; structure Ras; nanocluster; Raf; dimerization; Ras orientation; membrane; HVR; structure
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MDPI and ACS Style

Abankwa, D.; Gorfe, A.A. Mechanisms of Ras Membrane Organization and Signaling: Ras Rocks Again. Biomolecules 2020, 10, 1522. https://doi.org/10.3390/biom10111522

AMA Style

Abankwa D, Gorfe AA. Mechanisms of Ras Membrane Organization and Signaling: Ras Rocks Again. Biomolecules. 2020; 10(11):1522. https://doi.org/10.3390/biom10111522

Chicago/Turabian Style

Abankwa, Daniel; Gorfe, Alemayehu A. 2020. "Mechanisms of Ras Membrane Organization and Signaling: Ras Rocks Again" Biomolecules 10, no. 11: 1522. https://doi.org/10.3390/biom10111522

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