Understanding pathogenic single-nucleotide polymorphisms in multidomain proteins - Studies of isolated domains are not enough

Lucy G. Randles, Gwen J.S. Dawes, Beth G. Wensley, Annette Steward, Adrian A. Nickson, Jane Clarke*

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

    6 Citations (Scopus)

    Abstract

    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.

    Original languageEnglish
    Pages (from-to)1018-1027
    Number of pages10
    JournalFEBS Journal
    Volume280
    Issue number4
    DOIs
    Publication statusPublished - Feb 2013

    Keywords

    • disease-causing mutation
    • multidomain protein
    • pathogenic mutation
    • protein interface
    • single nucleotide polymorphism

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