Nanoclusters of Lipid-anchored Proteins in Membranes: How and where do they form? Abstract Recent studies have shown that lipid-anchored signaling proteins dynamically organize into nanoscale substructures on the plasma membrane. The resulting protein-lipid nanoclusters serve as hubs for high-fidelity signal transmission. However, the molecular basis of how nanoclusters form and distribute in heterogeneous membrane domains remains undetermined. As a result, it is unclear how nanoclusters of homologous proteins, such as the signaling switches H-ras and K-ras, segregate to different lipid domains. We hypothesize that this would be achieved by a combination of lipid-based and protein-based sorting mechanisms. We plan to test this hypothesis using multi-scale molecular simulations and theoretical approaches complemented by collaborative experiments. We will use the H- and K-ras oncoproteins as model systems. Ras nanoclusters have intriguing implications for unique mechanisms of signal regulation at the plasma membrane. Elucidating the mechanisms that drive the spatiotemporal organization of Ras nanoclusters will therefore lead to a better understanding of cell signaling. In addition, whil this proposal is focused on Ras, the approach and principles that are developed will be applicable for the study of any lipidated signaling protein. The broader impacts of the work include contributions to potential therapeutic strategies for targeting Ras nanodomains and the biophysics of coupled protein/lipid sorting.

Public Health Relevance

Ras nanoclusters have intriguing implications for unique mechanisms of signal regulation at the plasma membrane and may represent novel therapeutic targets to prevent defective Ras signaling, a common cause of many cancers. Elucidating the mechanisms that drive the spatiotemporal organization of Ras nanoclusters will lead to a better understanding of cell signaling and contribute to potential therapeutic strategies for targeting Ras nanodomains.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM100078-03
Application #
8725197
Study Section
Biochemistry and Biophysics of Membranes Study Section (BBM)
Program Officer
Chin, Jean
Project Start
2012-09-01
Project End
2017-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Biology
Type
Schools of Medicine
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77225
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Cho, Kwang-Jin; Casteel, Darren E; Prakash, Priyanka et al. (2016) AMPK and Endothelial Nitric Oxide Synthase Signaling Regulates K-Ras Plasma Membrane Interactions via Cyclic GMP-Dependent Protein Kinase 2. Mol Cell Biol 36:3086-3099
Prakash, Priyanka; Zhou, Yong; Liang, Hong et al. (2016) Oncogenic K-Ras Binds to an Anionic Membrane in Two Distinct Orientations: A Molecular Dynamics Analysis. Biophys J 110:1125-38
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Li, Zhenlong; Gorfe, Alemayehu A (2015) Receptor-mediated membrane adhesion of lipid-polymer hybrid (LPH) nanoparticles studied by dissipative particle dynamics simulations. Nanoscale 7:814-24
Prakash, Priyanka; Sayyed-Ahmad, Abdallah; Gorfe, Alemayehu A (2015) pMD-Membrane: A Method for Ligand Binding Site Identification in Membrane-Bound Proteins. PLoS Comput Biol 11:e1004469
Prakash, Priyanka; Hancock, John F; Gorfe, Alemayehu A (2015) Binding hotspots on K-ras: consensus ligand binding sites and other reactive regions from probe-based molecular dynamics analysis. Proteins 83:898-909
Lin, Xubo; Li, Zhenlong; Gorfe, Alemayehu A (2015) Reversible Effects of Peptide Concentration and Lipid Composition on H-Ras Lipid Anchor Clustering. Biophys J 109:2467-70
Prakash, Priyanka; Gorfe, Alemayehu A (2014) Overview of simulation studies on the enzymatic activity and conformational dynamics of the GTPase Ras. Mol Simul 40:839-847

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