Ras Conformational Ensembles, Allostery, and Signaling

Shaoyong Lu, Hyunbum Jang, Serena Muratcioglu, Attila Gursoy, Ozlem Keskin, Ruth Nussinov*, Jian Zhang

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

Abstract

Ras proteins are classical members of small GTPases that function as molecular switches by alternating between inactive GDP-bound and active GTP-bound states. Ras activation is regulated by guanine nucleotide exchange factors that catalyze the exchange of GDP by GTP, and inactivation is terminated by GTPase-activating proteins that accelerate the intrinsic GTP hydrolysis rate by orders of magnitude. In this review, we focus on data that have accumulated over the past few years pertaining to the conformational ensembles and the allosteric regulation of Ras proteins and their interpretation from our conformational landscape standpoint. The Ras ensemble embodies all states, including the ligand-bound conformations, the activated (or inactivated) allosteric modulated states, post-translationally modified states, mutational states, transition states, and nonfunctional states serving as a reservoir for emerging functions. The ensemble is shifted by distinct mutational events, cofactors, post-translational modifications, and different membrane compositions. A better understanding of Ras biology can contribute to therapeutic strategies.

Original languageEnglish
Pages (from-to)6607-6665
Number of pages59
JournalChemical Reviews
Volume116
Issue number11
DOIs
StatePublished - 8 Jun 2016

Funding

FundersFunder number
Collaborative Innovation Center of Systems Biomedicine
TUBITAK114M196
US government
National Institutes of HealthHHSN261200800001E
U.S. Department of Health and Human Services
National Cancer InstituteZIABC010441
Frederick National Laboratory for Cancer Research
National Natural Science Foundation of China81473137, 81322046, 81302698
Program for New Century Excellent Talents in UniversityNCET-12-0355
Shanghai Minhang Health And Family Planning Commission20154Y0058
National Basic Research Program of China (973 Program)2015CB910403
Shanghai Rising-Star Program13QA1402300

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