Cadherin clusters stabilized by a combination of specific and nonspecific cis-interactions

Author:

Thompson Connor J1ORCID,Su Zhaoqian2ORCID,Vu Vinh H3,Wu Yinghao2ORCID,Leckband Deborah E34,Schwartz Daniel K1ORCID

Affiliation:

1. Department of Chemical and Biological Engineering, University of Colorado Boulder, Boulder, United States

2. Department of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, United States

3. Department of Biochemistry and University of Illinois, Urbana-Champaign, Urbana, United States

4. Department of Chemical and Biomolecular Engineering, University of Illinois, Urbana-Champaign, Urbana, United States

Abstract

We demonstrate a combined experimental and computational approach for the quantitative characterization of lateral interactions between membrane-associated proteins. In particular, weak, lateral (cis) interactions between E-cadherin extracellular domains tethered to supported lipid bilayers, were studied using a combination of dynamic single-molecule Förster Resonance Energy Transfer (FRET) and kinetic Monte Carlo (kMC) simulations. Cadherins are intercellular adhesion proteins that assemble into clusters at cell-cell contacts through cis- and trans- (adhesive) interactions. A detailed and quantitative understanding of cis-clustering has been hindered by a lack of experimental approaches capable of detecting and quantifying lateral interactions between proteins on membranes. Here single-molecule intermolecular FRET measurements of wild-type E-cadherin and cis-interaction mutants combined with simulations demonstrate that both nonspecific and specific cis-interactions contribute to lateral clustering on lipid bilayers. Moreover, the intermolecular binding and dissociation rate constants are quantitatively and independently determined, demonstrating an approach that is generalizable for other interacting proteins.

Funder

National Institute of General Medical Sciences

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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