A distributed residue network permits conformational binding specificity in a conserved family of actin remodelers

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...

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Autores principales:	Theresa Hwang, Sara S Parker, Samantha M Hill, Meucci W Ilunga, Robert A Grant, Ghassan Mouneimne, Amy E Keating
Formato:	article
Lenguaje:	EN
Publicado:	eLife Sciences Publications Ltd 2021
Materias:	protein-protein interaction short linear motif epistasis actin Ena/VASP protein specificity Medicine R Science Q Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/85b0b8918f554dc58611c73b71fa31cd
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spelling	oai:doaj.org-article:85b0b8918f554dc58611c73b71fa31cd2021-12-02T15:42:49ZA distributed residue network permits conformational binding specificity in a conserved family of actin remodelers10.7554/eLife.706012050-084Xe70601https://doaj.org/article/85b0b8918f554dc58611c73b71fa31cd2021-12-01T00:00:00Zhttps://elifesciences.org/articles/70601https://doaj.org/toc/2050-084XMetazoan 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.Theresa HwangSara S ParkerSamantha M HillMeucci W IlungaRobert A GrantGhassan MouneimneAmy E KeatingeLife Sciences Publications Ltdarticleprotein-protein interactionshort linear motifepistasisactinEna/VASPprotein specificityMedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	protein-protein interaction short linear motif epistasis actin Ena/VASP protein specificity Medicine R Science Q Biology (General) QH301-705.5
spellingShingle	protein-protein interaction short linear motif epistasis actin Ena/VASP protein specificity Medicine R Science Q Biology (General) QH301-705.5 Theresa Hwang Sara S Parker Samantha M Hill Meucci W Ilunga Robert A Grant Ghassan Mouneimne Amy E Keating A distributed residue network permits conformational binding specificity in a conserved family of actin remodelers
description	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.
format	article
author	Theresa Hwang Sara S Parker Samantha M Hill Meucci W Ilunga Robert A Grant Ghassan Mouneimne Amy E Keating
author_facet	Theresa Hwang Sara S Parker Samantha M Hill Meucci W Ilunga Robert A Grant Ghassan Mouneimne Amy E Keating
author_sort	Theresa Hwang
title	A distributed residue network permits conformational binding specificity in a conserved family of actin remodelers
title_short	A distributed residue network permits conformational binding specificity in a conserved family of actin remodelers
title_full	A distributed residue network permits conformational binding specificity in a conserved family of actin remodelers
title_fullStr	A distributed residue network permits conformational binding specificity in a conserved family of actin remodelers
title_full_unstemmed	A distributed residue network permits conformational binding specificity in a conserved family of actin remodelers
title_sort	distributed residue network permits conformational binding specificity in a conserved family of actin remodelers
publisher	eLife Sciences Publications Ltd
publishDate	2021
url	https://doaj.org/article/85b0b8918f554dc58611c73b71fa31cd
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A distributed residue network permits conformational binding specificity in a conserved family of actin remodelers

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