Understanding pathogenic single‐nucleotide polymorphisms in multidomain proteins – studies of isolated domains are not enough
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 stu...
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Published in | The FEBS journal Vol. 280; no. 4; pp. 1018 - 1027 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
England
Blackwell Publishing Ltd
01.02.2013
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Subjects | |
Online Access | Get full text |
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Summary: | 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.
We investigate pathogenic and non‐pathogenic mutations occurring at the boundaries of human spectrin repeats. We show that mutations in isolated domains do not correlate with disease; however, in a tandem model system, pathogenic mutations disrupt stabilizing interactions between domains. This causes a much larger destabilisation than expected and demonstrates the importance of studying such mutations in the correct protein context |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1742-464X 1742-4658 |
DOI: | 10.1111/febs.12094 |