FERM domains recruit ample PI(4,5)P2s to form extensive protein-membrane attachments


The four-point-one ezrin-radixin-moesin homology (FERM) protein domain is a multifunctional protein-lipid binding site, constituting an integral part of numerous membrane-associated proteins. Its interaction with the lipid phosphatidylinositol-4,5-bisphosphate (PIP2), located at the inner leaflet of eukaryotic plasma membranes, is important for localization, anchorage, and activation of FERM-containing proteins. FERM-PIP2 complexes structurally determined so far exclusively feature a 1:1 binding stoichiometry of protein and lipid, with a few basic FERM residues neutralizing the −4 charge of the bound PIP2. Whether this picture from static crystal structures also applies to the dynamic interaction of FERM domains on PIP2 membranes is unknown. We here quantified the stoichiometry of FERM-PIP2 binding in a lipid bilayer using atomistic molecular dynamics simulations and experiments on solid supported membranes for the FERM domains of focal adhesion kinase and ezrin. In contrast to the structural data, we find much higher average stoichiometries of FERM-PIP2 binding, amounting to 1:3 or 1:4 ratios, respectively. In simulations, the full set of basic residues at the membrane interface, 7 and 15 residues for focal adhesion kinase and ezrin, respectively, engages in PIP2 interactions. In addition, Na ions enter the FERM-membrane binding interface, compensating negative PIP2 charges in case of high charge surpluses from bound PIP2. We propose the multivalent binding of FERM domains to PIP2 in lipid bilayers to significantly enhance the stability of FERM-membrane binding and to render the FERM-membrane linkage highly adjustable.

SEEK ID: https://publications.h-its.org/publications/1649

DOI: 10.1016/j.bpj.2023.02.027

Research Groups: Molecular Biomechanics

Publication type: Journal

Journal: Biophysical Journal

Publisher: Elsevier BV

Citation: Biophysical Journal

Date Published: 21st Feb 2023


Registered Mode: manually

Authors: Thomas Ehret, Tim Heißenberg, Svenja de Buhr, Camilo Aponte-Santamaría, Claudia Steinem, Frauke Gräter

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Ehret, T., Heißenberg, T., de Buhr, S., Aponte-Santamaría, C., Steinem, C., & Gräter, F. (2023). FERM domains recruit ample PI(4,5)P2s to form extensive protein-membrane attachments. In Biophysical Journal (Vol. 122, Issue 7, pp. 1325–1333). Elsevier BV. https://doi.org/10.1016/j.bpj.2023.02.027

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Created: 3rd Apr 2023 at 08:16

Last updated: 5th Mar 2024 at 21:25

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