BACR educational session – Protein structure/disorder-function relationships in the analysis of cancer mutations

Host: M. Madan Babu, MRC Laboratory of Molecular Biology, Cambridge, UK
Host: Richard Bayliss, Astbury Centre for Structural Molecular Biology, University of Leeds


Room: Default Location

Sequencing of tumour samples provides insights into the genetics of an individual’s disease aetiology and progression, improves the accuracy of prognosis and informs treatment decisions. These studies can also identify novel drivers of poor outcome in subsets of patients, lead to molecular-level insights into disease and provide new targets for drug discovery.

Mutations in protein coding regions may result in loss or gain of function, or be neutral, and their classification requires an understanding of how proteins function at the molecular level. Classically, understanding protein function has been dominated by the structure-function paradigm. That is, proteins adopt defined structures, which is important to achieve their function. However, in recent years, a large fraction of polypeptide sequences do not adopt defined tertiary structure (disordered regions) but are nevertheless functional. Such segments contain linear motifs and post-translational modification that can mediate protein interactions and integrate signaling inputs, all of which eventually regulate protein function and protein stability in the cell. Indeed, several disease-causing mutations have been recently discovered to reside within such regions. Thus, to infer the impact of cancer mutations, we must revisit the structure-function relationships that determine the consequence of mutations in folded regions, and extend this concept to disorder-function relationships.

This consideration becomes critical in evaluating the driver fusion proteins such as EML4-ALK that are generated by chromosomal rearrangements. The combination of functional domains and disordered segments in the fusion is distinct from either parent protein and the structural and functional properties of individual protein regions may be altered depending on the specific breakpoint. This can generate dependencies that provide opportunities for selective targeting.

This workshop is aimed at biologists and clinicians from all backgrounds. It will first introduce the disorder-function paradigm and will include a how-to guide on web-based resources that aid in the classification of mutations. A case study using the EML4-ALK driver fusion as a paradigm will also be presented.