Higher-order transient membrane protein structures

Zhang Y, Mazal H, Mandala VS, Pérez-Mitta G, Sondoghdar V, Haselwandter CA, MacKinnon R (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Proceedings of the National Academy of Sciences of the United States of America National Academy of Sciences

Book Volume: 122

Article Number: e2421275121

Journal Issue: 1

DOI: 10.1073/pnas.2421275121

Abstract

This study shows that five membrane proteins—three GPCRs, an ion channel, and an enzyme—form self-clusters under natural expression levels in a cardiac-derived cell line. The cluster size distributions imply that these proteins self-oligomerize reversibly through weak interactions. When the concentration of the proteins is increased through heterologous expression, the cluster size distributions approach a critical distribution at which point a phase transition occurs, yielding larger bulk phase clusters. A thermodynamic model like that explaining micellization of amphiphiles and lipid membrane formation accounts for this behavior. We propose that many membrane proteins exist as oligomers that form through weak interactions, which we call higher-order transient structures (HOTS). The key characteristics of HOTS are transience, molecular specificity, and a monotonically decreasing size distribution that may become critical at high concentrations. Because molecular specificity invokes self-recognition through protein sequence and structure, we propose that HOTS are genetically encoded supramolecular units.

Involved external institutions

Rockefeller University US United States (USA) (US) Max-Planck-Institut für die Physik des Lichts (MPL) / Max Planck Institute for the Science of Light DE Germany (DE) University of Southern California (USC) US United States (USA) (US)

How to cite

APA:

Zhang, Y., Mazal, H., Mandala, V.S., Pérez-Mitta, G., Sondoghdar, V., Haselwandter, C.A., & MacKinnon, R. (2025). Higher-order transient membrane protein structures. Proceedings of the National Academy of Sciences of the United States of America, 122(1). https://doi.org/10.1073/pnas.2421275121

MLA:

Zhang, Yuxi, et al. "Higher-order transient membrane protein structures." Proceedings of the National Academy of Sciences of the United States of America 122.1 (2025).

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