Characterising the consequences of naturally occurring nucleotide changes is a powerful approach to the identification of amino acid residues that are critical to protein function. While, numerous computational tools have been developed to predict variant effects in-silico, these have variable accuracy and rarely take into account protein three-dimensional structures.
Here we propose to combine experimental and computational methods to identify the amino acid substitutions that are more likely to de-stabilize the structure of multi-protein complexes. As the discrimination between benign and deleterious changes can be especially challenging for immune genes, the project will focus on variants that affect inflammatory proteins.
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Mahil SK, Catapano M, Di Meglio P, Dand N, Ahlfors H, Carr IM, Smith CH, Trembath RC, Peakman M, Wright J, Ciccarelli F, Barker JN, Capon F. An analysis of IL-36 signature genes and individuals with IL1RL2 knockout mutations validates IL-36 as a psoriasis therapeutic target. Science Translational Medicine, 2017 9:eaan2514
Laddach A, Ng JCF, Fraternali F. Pathogenic missense protein variants affect different functional pathways and proteomic features than healthy population variants. PLoS Biology 2021 19(4):e3001207