Interrogating protein sequence plasticity and function conservation at the outer limits of the twilight zone

Renos Savva (primary)
Department of Biological Sciences
Birkbeck
Mark Williams (secondary)
Department of Biological Sciences
Birkbeck

Abstract

A protein’s function is intimately related to its three-dimensional folded structure yet apparently unrelated structures can achieve equivalent functionality. The three distinct families of virus-encoded proteins that inhibit the DNA-repair enzyme uracil-DNA glycosylase by mimicking the appearance of DNA at their surface provide an opportunity to investigate the limits of sequence plasticity. We will use a combination of synthetic gene libraries coupled to an in vivo functional assay, adding insights from structural biology and state-of-the art computation to explore the limits of sequence variation of these inhibitors. Our aims are to evaluate the computational methods and better understand viral evolution.


References

1 Architecturally diverse proteins converge on an analogous mechanism to inactivate Uracil-DNA glycosylase. Cole et al. (2013) Nucleic Acids. Res. 41, 8760–8775. doi:10.1093/nar/gkt633
2 https://peptone.io/
3 Co‐Evolutionary Fitness Landscapes for Sequence Design. Tian et al. (2018) Angewante Chemie 57, 5674-5678. doi:10.1002/anie.201713220
4 Mutation effects predicted from sequence co-variation. Hopf et al. (2017) Nat. Biotechnol 35, 128-135. doi: 10.1038/nbt.3769
5 https://www.dwavesys.com


BBSRC Area
Molecules, cells and industrial biotechnology
Area of Biology
EvolutionStructural Biology
Techniques & Approaches
BiochemistryBioinformaticsBiophysicsMolecular BiologySimulation / Modelling