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Speaker: Dr Joseph Chi-fung Ng, Post-doctoral Research Associate, Fraternali Lab, The Randall Centre for Cell and Molecular Biophysics
Pathogenicity, biophysical damage and the ‘dark matter’ of protein mutational landscape
Host: Franca Fraternali
Abstract: Dedicated experiments, in silico predictors and analyses of disease cohorts have annotated a great number of protein mutations as pathogenic. Many pathogenic mutations render proteins unstable and therefore affect function, however not all destabilising mutations are deemed pathogenic. I will present some attempts to understand biophysical features governing the distribution of mutations across the human proteome. Pathogenic variants tend to localise to the cores and interaction interfaces of abundant, stable proteins. We show that even in large mutation databases there is a depletion of damaging mutations, probably a result of purifying selection. Using in vitro and in silico saturation mutagenesis data we probe such ‘dark matter’ of the mutational landscape, identifying damaging mutations which (a) alter protein physicochemical characteristics and (b) are identifiable by specific mutable DNA motifs. These analyses mine features which help to separate disease association from the true impact mutations bring to protein stability/activity.