Global and Local Effects in Lipid-Mediated Interactions between Peripheral and Integral Membrane Proteins.

Published

May 30, 2025

Author(s)

Tatiana Rostovtseva, David Hoogerheide, William Milhizer, Sergey M. Bezrukov

Abstract

Amphitropic proteins (APs) are a subfamily of water-soluble peripherally membrane-bound proteins that interact directly with the lipid membrane rather than with intrinsic membrane proteins and are therefore strongly influenced by membrane properties. When an AP interacts with a membrane containing an integral membrane protein, a ternary protein-lipid-protein system is created. Even in the absence of direct interactions between the amphitropic and integral proteins, the two proteins can affect each other by modifying lipid membrane properties, either at the global (i.e., whole-membrane) or local (i.e., confined to a small area around the bound or integrated protein) scale. These lipid-mediated protein-protein interactions are indirect and, therefore, difficult to elucidate; independent experimental data are required to report on each individual interaction to comprehend the whole system. Examples for which comprehensive data are available are remarkably rare. Here, we describe how these difficulties could be surmounted by using the channel-forming integral membrane protein gramicidin A (grA) reconstituted in a planar lipid membrane and exposed to the amphitropic proteins dimeric tubulin or α-synuclein. Importantly, there are no known direct interactions between these APs and grA, thus revealing the role of the lipid membrane. The tubulin-lipid interaction mechanism is well studied; combined with the self-reporting properties of the grA channel, the effect of tubulin on the properties of the lipid membrane can be understood. We also discuss the converse relationship, where the presence of the grA conducting dimer alters the local membrane curvature and creates binding sites for tubulin in an otherwise inert membrane composition.

Citation

Frontiers in Molecular Biosciences

Volume

12

Pub Type

Journals

Download Paper

https://doi.org/10.3389/fmolb.2025.1605772

Local Download

Keywords

Tubulin, alpha-synuclein, gramicidin A, planar lipid membranes, ion channel, amphitropic proteins, protein-lipid interactions, lipid packing stress

Citation

Rostovtseva, T. , Hoogerheide, D. , Milhizer, W. and Bezrukov, S. (2025), Global and Local Effects in Lipid-Mediated Interactions between Peripheral and Integral Membrane Proteins., Frontiers in Molecular Biosciences, [online], https://doi.org/10.3389/fmolb.2025.1605772, https://tsapps.nist.gov/publication/get_pdf.cfm?pub_id=959915 (Accessed July 24, 2025)