Ankyrin repeats in context with human population variation.

Ankyrin protein repeats bind to a wide range of substrates and are one of the most common protein motifs in nature. Here, we collate a high-quality alignment of 7,407 ankyrin repeats and examine for the first time, the distribution of human population variants from large-scale sequencing of healthy...

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Autores principales:	Javier S Utgés, Maxim I Tsenkov, Noah J M Dietrich, Stuart A MacGowan, Geoffrey J Barton
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/6338f9ce25324411a491b998c87e7f25
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spelling	oai:doaj.org-article:6338f9ce25324411a491b998c87e7f252021-12-02T19:58:01ZAnkyrin repeats in context with human population variation.1553-734X1553-735810.1371/journal.pcbi.1009335https://doaj.org/article/6338f9ce25324411a491b998c87e7f252021-08-01T00:00:00Zhttps://doi.org/10.1371/journal.pcbi.1009335https://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Ankyrin protein repeats bind to a wide range of substrates and are one of the most common protein motifs in nature. Here, we collate a high-quality alignment of 7,407 ankyrin repeats and examine for the first time, the distribution of human population variants from large-scale sequencing of healthy individuals across this family. Population variants are not randomly distributed across the genome but are constrained by gene essentiality and function. Accordingly, we interpret the population variants in context with evolutionary constraint and structural features including secondary structure, accessibility and protein-protein interactions across 383 three-dimensional structures of ankyrin repeats. We find five positions that are highly conserved across homologues and also depleted in missense variants within the human population. These positions are significantly enriched in intra-domain contacts and so likely to be key for repeat packing. In contrast, a group of evolutionarily divergent positions are found to be depleted in missense variants in human and significantly enriched in protein-protein interactions. Our analysis also suggests the domain has three, not two surfaces, each with different patterns of enrichment in protein-substrate interactions and missense variants. Our findings will be of interest to those studying or engineering ankyrin-repeat containing proteins as well as those interpreting the significance of disease variants.Javier S UtgésMaxim I TsenkovNoah J M DietrichStuart A MacGowanGeoffrey J BartonPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 17, Iss 8, p e1009335 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Javier S Utgés Maxim I Tsenkov Noah J M Dietrich Stuart A MacGowan Geoffrey J Barton Ankyrin repeats in context with human population variation.
description	Ankyrin protein repeats bind to a wide range of substrates and are one of the most common protein motifs in nature. Here, we collate a high-quality alignment of 7,407 ankyrin repeats and examine for the first time, the distribution of human population variants from large-scale sequencing of healthy individuals across this family. Population variants are not randomly distributed across the genome but are constrained by gene essentiality and function. Accordingly, we interpret the population variants in context with evolutionary constraint and structural features including secondary structure, accessibility and protein-protein interactions across 383 three-dimensional structures of ankyrin repeats. We find five positions that are highly conserved across homologues and also depleted in missense variants within the human population. These positions are significantly enriched in intra-domain contacts and so likely to be key for repeat packing. In contrast, a group of evolutionarily divergent positions are found to be depleted in missense variants in human and significantly enriched in protein-protein interactions. Our analysis also suggests the domain has three, not two surfaces, each with different patterns of enrichment in protein-substrate interactions and missense variants. Our findings will be of interest to those studying or engineering ankyrin-repeat containing proteins as well as those interpreting the significance of disease variants.
format	article
author	Javier S Utgés Maxim I Tsenkov Noah J M Dietrich Stuart A MacGowan Geoffrey J Barton
author_facet	Javier S Utgés Maxim I Tsenkov Noah J M Dietrich Stuart A MacGowan Geoffrey J Barton
author_sort	Javier S Utgés
title	Ankyrin repeats in context with human population variation.
title_short	Ankyrin repeats in context with human population variation.
title_full	Ankyrin repeats in context with human population variation.
title_fullStr	Ankyrin repeats in context with human population variation.
title_full_unstemmed	Ankyrin repeats in context with human population variation.
title_sort	ankyrin repeats in context with human population variation.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/6338f9ce25324411a491b998c87e7f25
work_keys_str_mv	AT javiersutges ankyrinrepeatsincontextwithhumanpopulationvariation AT maximitsenkov ankyrinrepeatsincontextwithhumanpopulationvariation AT noahjmdietrich ankyrinrepeatsincontextwithhumanpopulationvariation AT stuartamacgowan ankyrinrepeatsincontextwithhumanpopulationvariation AT geoffreyjbarton ankyrinrepeatsincontextwithhumanpopulationvariation
_version_	1718375779966910464

Ankyrin repeats in context with human population variation.

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