A distributed residue network permits conformational binding specificity in a conserved family of actin remodelers
Name
elife-70601-v1.pdf
Description
Published version
Size
6.79 MB
Format
Adobe PDF
Checksum (MD5)
90cd963a34f6ac4a0f357923790f8b02
Author(s)
Hwang, Theresa
Parker, Sara S
Hill, Samantha M
Ilunga, Meucci W
Grant, Robert A
Mouneimne, Ghassan
Keating, Amy E
Date Issued
2021
Journal
eLife
Publisher
eLife Sciences Publications, Ltd
Citation
Hwang, Theresa, Parker, Sara S, Hill, Samantha M, Ilunga, Meucci W, Grant, Robert A et al. 2021. "A distributed residue network permits conformational binding specificity in a conserved family of actin remodelers." eLife, 10.
Version
Final published version
Abstract
Metazoan proteomes contain many paralogous proteins that have evolved distinct functions. The Ena/VASP family of actin regulators consists of three members that share an EVH1 interaction domain with a 100 % conserved binding site. A proteome-wide screen revealed photoreceptor cilium actin regulator (PCARE) as a high-affinity ligand for ENAH EVH1. Here, we report the surprising observation that PCARE is ~100-fold specific for ENAH over paralogs VASP and EVL and can selectively bind ENAH and inhibit ENAH-dependent adhesion in cells. Specificity arises from a mechanism whereby PCARE stabilizes a conformation of the ENAH EVH1 domain that is inaccessible to family members VASP and EVL. Structure-based modeling rapidly identified seven residues distributed throughout EVL that are sufficient to differentiate binding by ENAH vs. EVL. By exploiting the ENAH-specific conformation, we rationally designed the tightest and most selective ENAH binder to date. Our work uncovers a conformational mechanism of interaction specificity that distinguishes highly similar paralogs and establishes tools for dissecting specific Ena/VASP functions in processes including cancer cell invasion.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Terms of Use
Creative Commons Attribution 4.0 International license
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DOI of Published Version
https://doi.org/10.7554/ELIFE.70601
