title: Anatomy of protein disorder, flexibility and disease-related mutations.
abstract: Integration of protein structural information with human genetic variation and pathogenic mutations is essential to understand molecular mechanisms associated with the effects of polymorphisms on protein interactions and cellular processes. We investigate occurrences of non-synonymous SNPs in ordered and disordered protein regions by systematic mapping of common variants and disease-related SNPs onto these regions. We show that common variants accumulate in disordered regions; conversely pathogenic variants are significantly depleted in disordered regions. These different occurrences of pathogenic and common SNPs can be attributed to a negative selection on random mutations in structurally highly constrained regions. New approaches in the study of quantitative effects of pathogenic-related mutations should effectively account for all the possible contexts and relative functional constraints in which the sequence variation occurs.
authors: Randall Division of Cell and Molecular Biophysics, King's College London London, UK.
authors: Hui-Chun
authors: HC
authors: Lu
authors: Randall Division of Cell and Molecular Biophysics, King's College London London, UK ; Department of Haematological Medicine, King's College London London, UK.
authors: Sun Sook
authors: SS
authors: Chung
authors: Randall Division of Cell and Molecular Biophysics, King's College London London, UK ; School of Biological and Chemical Sciences, Queen Mary University of London London, UK.
authors: Arianna
authors: A
authors: Fornili
authors: Randall Division of Cell and Molecular Biophysics, King's College London London, UK.
authors: Franca
authors: F
authors: Fraternali
keywords: disease-related mutations; non-synonymous SNPs; order-disorder propensity; protein disorder; protein flexibility