Structural design principles for specific ultra-high affinity interactions between colicins/pyocins and immunity proteins

Abstract The interactions of the antibiotic proteins colicins/pyocins with immunity proteins is a seminal model system for studying protein–protein interactions and specificity. Yet, a precise and quantitative determination of which structural elements and residues determine their binding affinity a...

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Autores principales:	Avital Shushan, Mickey Kosloff
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/eebc68ecefcd47f48e1af52640e17f11
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spelling	oai:doaj.org-article:eebc68ecefcd47f48e1af52640e17f112021-12-02T14:03:46ZStructural design principles for specific ultra-high affinity interactions between colicins/pyocins and immunity proteins10.1038/s41598-021-83265-22045-2322https://doaj.org/article/eebc68ecefcd47f48e1af52640e17f112021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-83265-2https://doaj.org/toc/2045-2322Abstract The interactions of the antibiotic proteins colicins/pyocins with immunity proteins is a seminal model system for studying protein–protein interactions and specificity. Yet, a precise and quantitative determination of which structural elements and residues determine their binding affinity and specificity is still lacking. Here, we used comparative structure-based energy calculations to map residues that substantially contribute to interactions across native and engineered complexes of colicins/pyocins and immunity proteins. We show that the immunity protein α1–α2 motif is a unique structurally-dissimilar element that restricts interaction specificity towards all colicins/pyocins, in both engineered and native complexes. This motif combines with a diverse and extensive array of electrostatic/polar interactions that enable the exquisite specificity that characterizes these interactions while achieving ultra-high affinity. Surprisingly, the divergence of these contributing colicin residues is reciprocal to residue conservation in immunity proteins. The structurally-dissimilar immunity protein α1–α2 motif is recognized by divergent colicins similarly, while the conserved immunity protein α3 helix interacts with diverse colicin residues. Electrostatics thus plays a key role in setting interaction specificity across all colicins and immunity proteins. Our analysis and resulting residue-level maps illuminate the molecular basis for these protein–protein interactions, with implications for drug development and rational engineering of these interfaces.Avital ShushanMickey KosloffNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Avital Shushan Mickey Kosloff Structural design principles for specific ultra-high affinity interactions between colicins/pyocins and immunity proteins
description	Abstract The interactions of the antibiotic proteins colicins/pyocins with immunity proteins is a seminal model system for studying protein–protein interactions and specificity. Yet, a precise and quantitative determination of which structural elements and residues determine their binding affinity and specificity is still lacking. Here, we used comparative structure-based energy calculations to map residues that substantially contribute to interactions across native and engineered complexes of colicins/pyocins and immunity proteins. We show that the immunity protein α1–α2 motif is a unique structurally-dissimilar element that restricts interaction specificity towards all colicins/pyocins, in both engineered and native complexes. This motif combines with a diverse and extensive array of electrostatic/polar interactions that enable the exquisite specificity that characterizes these interactions while achieving ultra-high affinity. Surprisingly, the divergence of these contributing colicin residues is reciprocal to residue conservation in immunity proteins. The structurally-dissimilar immunity protein α1–α2 motif is recognized by divergent colicins similarly, while the conserved immunity protein α3 helix interacts with diverse colicin residues. Electrostatics thus plays a key role in setting interaction specificity across all colicins and immunity proteins. Our analysis and resulting residue-level maps illuminate the molecular basis for these protein–protein interactions, with implications for drug development and rational engineering of these interfaces.
format	article
author	Avital Shushan Mickey Kosloff
author_facet	Avital Shushan Mickey Kosloff
author_sort	Avital Shushan
title	Structural design principles for specific ultra-high affinity interactions between colicins/pyocins and immunity proteins
title_short	Structural design principles for specific ultra-high affinity interactions between colicins/pyocins and immunity proteins
title_full	Structural design principles for specific ultra-high affinity interactions between colicins/pyocins and immunity proteins
title_fullStr	Structural design principles for specific ultra-high affinity interactions between colicins/pyocins and immunity proteins
title_full_unstemmed	Structural design principles for specific ultra-high affinity interactions between colicins/pyocins and immunity proteins
title_sort	structural design principles for specific ultra-high affinity interactions between colicins/pyocins and immunity proteins
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/eebc68ecefcd47f48e1af52640e17f11
work_keys_str_mv	AT avitalshushan structuraldesignprinciplesforspecificultrahighaffinityinteractionsbetweencolicinspyocinsandimmunityproteins AT mickeykosloff structuraldesignprinciplesforspecificultrahighaffinityinteractionsbetweencolicinspyocinsandimmunityproteins
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Structural design principles for specific ultra-high affinity interactions between colicins/pyocins and immunity proteins

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