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 do not fully exploit information on protein three-dimensional structure.
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.
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 JC, Chung SS, Fraternali F. (2018). Genetic variants and protein-protein interactions: a multidimensional network-centric view. Curr Opin Struct Biol. 2018 Jan 4;50:82-90. doi: 10.1016/j.sbi.2017.12.006.
Hussain S, Berki DM, Choon SE, Burden AD, Allen MH, Arostegui JI, Chaves A, Duckworth M, Irvine AD, Mockenhaupt M, Navarini AA, Seyger MMB, Soler-Palacin P, Prins C, Valeyrie-Allanore L, Vicente MA, Trembath RC, Smith CH, Barker JN, Capon F. IL36RN mutations define a severe auto-inflammatory phenotype of generalized pustular psoriasis. J Allergy Clin Immunol 2015 135:1067-1070
Chung SS, Pandini A, Annibale A, Coolen AC, Thomas NS, Fraternali F. Bridging topological and functional information in protein interaction networks by short loops profiling. Sci Rep. 2015 Feb 23;5:8540. doi: 10.1038/srep08540.