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Understanding pathogenic single‐nucleotide polymorphisms in multidomain proteins – studies of isolated domains are not enough
Author(s) -
Randles Lucy G.,
Dawes Gwen J. S.,
Wensley Beth G.,
Steward Annette,
Nickson Adrian A.,
Clarke Jane
Publication year - 2013
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.12094
Subject(s) - genetics , point mutation , biology , mutation , context (archaeology) , domain (mathematical analysis) , computational biology , single point , protein domain , spectrin , human disease , gene , computer science , paleontology , mathematical analysis , mathematics , cytoskeleton , artificial intelligence , cell , triz
Studying the effects of pathogenic mutations is more complex in multidomain proteins when compared with single domains: mutations occurring at domain boundaries may have a large effect on a neighbouring domain that will not be detected in a single‐domain system. To demonstrate this, we present a study that utilizes well‐characterized model protein domains from human spectrin to investigate the effect of disease‐ and non‐disease‐causing single point mutations occurring at the boundaries of human spectrin repeats. Our results show that mutations in the single domains have no clear correlation with stability and disease; however, when studied in a tandem model system, the disease‐causing mutations are shown to disrupt stabilizing interactions that exist between domains. This results in a much larger decrease in stability than would otherwise have been predicted, and demonstrates the importance of studying such mutations in the correct protein context.