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

作者：Randles Lucy G; Dawes Gwen J S; Wensley Beth G; Steward Annette; Nickson Adrian A; Clarke Jane^*

来源：FEBS Journal, 2013, 280(4): 1018-1027.

DOI：10.1111/febs.12094

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

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.

• 出版日期2013-2