Structural highlights
Publication Abstract from PubMedMetazoan 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. A distributed residue network permits conformational binding specificity in a conserved family of actin remodelers.,Hwang T, Parker SS, Hill SM, Ilunga MW, Grant RA, Mouneimne G, Keating AE Elife. 2021 Dec 2;10. pii: 70601. doi: 10.7554/eLife.70601. PMID:34854809[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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