Ankyrin repeats in context with human population variation

• DOI: 10.1371/journal.pcbi.1009335
• Publication Date: 2021-08-24T18:16:12Z
• Authors: Javier S. Utgés; Maxim I. Tsenkov; Noah J. M. Dietrich; Stuart A. MacGowan; Geoffrey J. Barton
• Keywords: Ankyrin repeat; Ankyrin; Protein family

Ankyrin protein repeats bind to a wide range of substrates and are one the most common motifs in nature. Here, we collate high-quality alignment 7,407 ankyrin examine for first time, distribution human population variants from large-scale sequencing healthy individuals across this family. Population not randomly distributed genome but constrained by gene essentiality function. Accordingly, interpret context with evolutionary constraint structural features including secondary structure, accessibility protein-protein interactions 383 three-dimensional structures repeats. We find five positions that highly conserved homologues also depleted missense within population. These significantly enriched intra-domain contacts so likely be key repeat packing. In contrast, group evolutionarily divergent found interactions. Our analysis suggests domain has three, two surfaces, each different patterns enrichment protein-substrate variants. findings will interest those studying or engineering ankyrin-repeat containing proteins as well interpreting significance disease