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Visualizing the Conformational Dynamics of Membrane Receptors Using Single-Molecule FRET
Published on: August 17, 2022
Ras Conformational Ensembles, Allostery, and Signaling
Shaoyong Lu1,2, Hyunbum Jang2, Serena Muratcioglu
1Department of Pathophysiology, Shanghai Universities E-Institute for Chemical Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, School of Medicine , Shanghai, 200025, China.
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.
Insights
Ras proteins act as molecular switches, cycling between active and inactive states. This review explores their conformational ensembles and allosteric regulation, crucial for understanding Ras biology and developing therapies.
Area of Science:
- Biochemistry
- Molecular Biology
- Cell Signaling
Background:
- Ras proteins are small GTPases functioning as molecular switches.
- They alternate between inactive GDP-bound and active GTP-bound states.
- Regulation involves guanine nucleotide exchange factors and GTPase-activating proteins.
Purpose of the Study:
- To review recent data on Ras protein conformational ensembles.
- To explore the allosteric regulation of Ras proteins.
- To interpret findings from a conformational landscape perspective.
Main Methods:
- Literature review of accumulated data over recent years.
- Analysis of conformational ensembles.
- Examination of allosteric regulation mechanisms.
Main Results:
- The Ras ensemble encompasses diverse states: ligand-bound, allosteric modulated, post-translationally modified, mutational, transition, and nonfunctional states.
- Mutations, cofactors, post-translational modifications, and membrane composition influence the Ras ensemble.
- Conformational landscapes provide a framework for understanding Ras dynamics.
Conclusions:
- Understanding Ras conformational ensembles and allosteric regulation is key to deciphering Ras biology.
- This knowledge can inform the development of targeted therapeutic strategies for Ras-related diseases.
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