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Related Experiment Video

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Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods

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Direct Modulators of K-Ras-Membrane Interactions.

Johannes Morstein¹, Rebika Shrestha², Que N Van²

¹Department of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute, University of California, San Francisco, California 94158, United States.

ACS Chemical Biology

|August 14, 2023

Summary

This summary is machine-generated.

Researchers modulated protein-membrane interactions (PMIs) by conjugating a lipid tail to a K-Ras(G12C) binder. This strategy alters K-Ras(G12C) conformation and cell membrane interactions, impacting signaling pathways.

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Area of Science:

Biochemistry
Cell Biology
Molecular Pharmacology

Background:

Protein-membrane interactions (PMIs) are crucial for cellular signaling, particularly in initiating signal transduction cascades.
Transient and dynamic PMIs regulate signaling hotspots at the inner plasma membrane leaflet.

Purpose of the Study:

To develop a method for directly targeting and modulating protein-membrane interactions.
To investigate the impact of lipid conjugation on K-Ras(G12C) behavior and cellular signaling.

Main Methods:

Conjugation of a medium-chain lipid tail to the K-Ras(G12C) covalent binder MRTX849.
Molecular dynamics (MD) simulations and NMR studies to analyze conformational changes.
Cellular assays to assess K-Ras(G12C) lateral mobility and nanocluster formation.

Main Results:

Lipid conjugation successfully modulated PMIs by altering K-Ras(G12C) membrane orientation and conformation.
The modified binder restricted K-Ras(G12C) lateral mobility within cells.
Disruption of K-Ras(G12C) nanoclusters was observed.

Conclusions:

Lipid conjugation is a viable strategy to directly modulate transient protein-membrane interactions.
This approach offers a potential method for developing targeted therapeutics by controlling protein localization and signaling.
The strategy may be broadly applicable to other proteins involved in transient PMIs.