Lam, Su Datt; (2018) A domain based protein structural modelling platform applied in the analysis of alternative splicing. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Functional families (FunFams) are a sub-classification of CATH protein domain superfamilies that cluster relatives likely to have very similar structures and functions. The functional purity of FunFams has been demonstrated by comparing against experimentally determined Enzyme Commission annotations and by checking whether known functional sites coincide with highly conserved residues in the multiple sequence alignments of FunFams. We hypothesised that clustering relatives into FunFams may help in protein structure modelling. In the first work chapter, we demonstrate the structural coherence of domains in FunFams. We then explore the usage of FunFams in protein monomer modelling. The FunFam based protocol produced higher percentages of good models compared to an HHsearch (the state-of-the-art HMM based sequence search tool) based protocol for both close and remote homologs. We developed a modelling pipeline that, utilises the FunFam protocol, and is able to model up to 70% of domain sequences from human and fly genomes. In the second work chapter, we explore the usage of FunFams in protein complex modelling. Our analysis demonstrated that domain-domain interfaces in FunFams tend to be conserved. The FunFam based complex modelling protocol produced significantly more good quality models when compared to a BLAST based protocol and slightly better than a HHsearch based protocol. In the final work chapter, we employ the FunFam based structural modelling tool to understand the implications of alternative splicing. We focused on isoforms derived from mutually exclusively exons (MXEs) for which there is more enriched in proteomics data. MXEs which could be mapped to structure show a significant tendency to be exposed to the solvent, are likely to exhibit a significant change in their physiochemical property and to lie close to a known/predicted functional sites. Our results suggest that MXE events may have a number of important roles in cells generally.

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