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 #
5R01GM100078-02
Application #
8535794
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
2013-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$278,692
Indirect Cost
$95,342
Name
University of Texas Health Science Center Houston
Department
Biology
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77225
Li, Hualin; Gorfe, Alemayehu A (2014) Membrane Remodeling by Surface-Bound Protein Aggregates: Insights from Coarse-Grained Molecular Dynamics Simulation. J Phys Chem Lett 5:1457-1462
Li, Zhenlong; Gorfe, Alemayehu A (2014) Modulation of a small two-domain lipid vesicle by linactants. J Phys Chem B 118:9028-36
Li, Zhenlong; Gorfe, Alemayehu A (2013) Deformation of a Two-domain Lipid Bilayer due to Asymmetric Insertion of Lipid-modified Ras Peptides. Soft Matter 9:
Li, Hualin; Gorfe, Alemayehu A (2013) Aggregation of lipid-anchored full-length H-Ras in lipid bilayers: simulations with the MARTINI force field. PLoS One 8:e71018
Prakash, Priyanka; Gorfe, Alemayehu A (2013) Lessons from computer simulations of Ras proteins in solution and in membrane. Biochim Biophys Acta 1830:5211-8