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Evolutionary roots of allosteric regulation of enzymes

  • Full or part time
    Dr L Pedro Carvalho
    Prof F Fraternali
  • Application Deadline
    Tuesday, November 12, 2019
  • Funded PhD Project (Students Worldwide)
    Funded PhD Project (Students Worldwide)

Project Description

A joint Crick-Imperial College London funded PhD position for the 2019 programme between the labs of Luiz Pedro Carvalho and Franc Fraternali.

Allosteric regulation of enzymes is one of the most ancient mechanism of flux control through biochemical pathways. In the last decades by a series of studies of several allosteric systems we have learnt how allosteric regulation takes place at atomic level and how protein motions couple remote ligand binding to conformational changes in the protein that ultimately regulate enzyme kinetics and metabolic flux. In contrast, we know very little about the evolutionary history of allostery. This project aims to address the fundamental question in biochemistry: how did enzymes evolve their allosteric communication networks? This knowledge will not only serve to inform on how proteins and more specifically enzymes evolved, but also help to design evolution-inspired modified enzymes and allosteric modulators. This might find applications in Human Medicine, Agriculture, Biotechnology and other fields of research.

In this project, the successful candidate will take advantage of both computational and experimental routes to define how evolution shapes allosteric regulation of enzymes. A combination of computational models, structural bioinformatics, protein biochemistry and enzymology will be used.

The project will be developed as a collaboration between the labs of Prof Franca Fraternali at King’s College London and the lab of Dr Luiz Pedro Carvalho at the Francis Crick Institute. The successful candidate is expected to work approximately 50% of the time in each lab. The proposed project aims at taking a novel approach to study the dynamics and evolution of allosteric regulation of metabolic enzymes. The novelty lies in the unraveling of the evolutionary history of networks of interactions within and between functionally cooperating enzyme’s domains. This is important because one can trace back the nature of the molecular mechanisms playing a role in initiating allosteric regulation of enzymes and therefore operate on these and design novel routes to enzyme regulation. Additionally, the works should allow to discern the contribution of different domains to the initiation of allosteric regulation and how protein interaction plays a role in this.

The successful candidate will work in both labs and attempt to (1) construct primary sequence alignments of all homologues; (2) calculate a phylogenetic tree that will be used to choose which homologues we will investigate; (3) clone codon adapted versions of ancient homologues of an important allosterically regulated metabolic enzyme, purify these proteins; (4) carry out a variety of enzymology experiments aimed at defining the kinetic and allosteric parameters of each homologue; (5) carry out molecular dynamics simulations to link the results obtained with specific residues, motions, interactions taking place. Analysis and interpretation of the computational and experimental data will allow us to define the evolutionary trajectories that shaped allostery in this system.


Candidate background
The candidate would ideally have background in biochemistry / chemistry / physics, with a strong interest in computational / bioinformatics analyses as well as protein biochemistry and enzymology. Knowledge of protein structure and function is essential. Previous experience in coding and scripting, and/or large-scale data analysis would be desirable. An interest in biological network analysis will also be desired. Experience in protein biochemistry would be desirable.

This 4-year PhD studentship is offered in Dr David Balchin’s Group based at the Francis Crick Institute (the Crick).

Talented and motivated students passionate about doing research are invited to apply for this PhD position. The successful applicant will join the Crick PhD Programme in September 2020 and will register for their PhD at King’s College London.

Applicants should hold or expect to gain a first/upper second-class honours degree or equivalent in a relevant subject and have appropriate research experience as part of, or outside of, a university degree course and/or a Masters degree in a relevant subject.

APPLICATIONS MUST BE MADE ONLINE VIA OUR WEBSITE (ACCESSIBLE VIA THE ‘APPLY NOW’ LINK ABOVE) BY 12:00 (NOON) 13 NOVEMBER 2019. APPLICATIONS WILL NOT BE ACCEPTED IN ANY OTHER FORMAT.

Funding Notes

Successful applicants will be awarded a non-taxable annual stipend of £22,000 plus payment of university tuition fees. Students of all nationalities are eligible to apply.

References

1. Chung, S. S., Pandini, A., Annibale, A., Coolen, A. C. C., Thomas, N. S. B. and Fraternali, F. (2015)

Bridging topological and functional information in protein interaction networks by short loops profiling.

Scientific Reports 5: 8540. PubMed abstract

2. Macpherson, J. A., Theisen, A., Masino, L., Fets, L., Driscoll, P. C., Encheva, V., . . . Anastasiou, D. (2019)

Functional cross-talk between allosteric effects of activating and inhibiting ligands underlies PKM2 regulation.

eLife 8: e45068. PubMed abstract

3. Stengel, F., Aebersold, R. and Robinson, C. V. (2012)

Joining forces: integrating proteomics and cross-linking with the mass spectrometry of intact complexes.

Molecular & Cellular Proteomics 11: R111.014027. PubMed abstract

4. Chen, Z. A. and Rappsilber, J. (2018)

Protein dynamics in solution by quantitative crosslinking/mass spectrometry.

Trends in Biochemical Sciences 43: 908-920. PubMed abstract

5. Schmidt, C., Macpherson, J. A., Lau, A. M., Tan, K. W., Fraternali, F. and Politis, A. (2017)

Surface accessibility and dynamics of macromolecular assemblies probed by covalent labeling mass spectrometry and integrative modeling.

Analytical Chemistry 89: 1459-1468. PubMed abstractj



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