title: Understanding pathogenic single-nucleotide polymorphisms in multidomain proteins--studies of isolated domains are not enough.
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.
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge, UK.
authors.forename: Lucy G
authors.initials: LG
authors.lastname: Randles
authors.forename: Gwen J S
authors.initials: GJ
authors.lastname: Dawes
authors.forename: Beth G
authors.initials: BG
authors.lastname: Wensley
authors.forename: Annette
authors.initials: A
authors.lastname: Steward
authors.forename: Adrian A
authors.initials: AA
authors.lastname: Nickson
authors.forename: Jane
authors.initials: J
authors.lastname: Clarke
mesh_terms: D006801:Humans; D007700:Kinetics; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D054730:Protein Interaction Domains and Motifs; D055550:Protein Stability; D058767:Protein Unfolding; D017422:Sequence Analysis, DNA; D013049:Spectrin / Q000737:chemistry / Q000235:genetics*; D013816:Thermodynamics
chemical_list: D013049:Spectrin