This sandwich placement will be based in the lab of Ian Taylor.
Project background and description
The project forms part of the current research program of the Taylor Macromolecular Structure Laboratory (http://www.crick.ac.uk/ian-taylor/) aimed at understanding the cellular functions of the HIV-1 restriction factor SAMHD1. SAMHD1 is a fundamentally important cellular protein that along with its antiviral activity and innate immunity function is responsible for the regulation of dNTP homeostasis and also associated with DNA repair pathways. Dysregulation or loss of SAMHD1 function is associated with both cancers and autoimmune diseases. Therefore, understanding the cellular functions of SAMHD1 is essential for development of new treatments against cancers, autoimmunity and inflammatory diseases. This project will initially involve cloning, expression and purification of a panel of newly discovered proteins that interact with SAMHD1 to modulate its enzymatic activities in DNA repair. In order to study the interaction of these proteins with SAMHD1 the student will then learn and use biophysical, hydrodynamic and spectroscopic techniques including analytical ultracentrifugation (AUC), multi-angle laser light scattering (MALLS) and Biacore to fully characterise the interaction of SAMHD1 with binding partners. The project is complementary to ongoing X-ray diffraction, cryo electron microscopy and enzymological studies being undertaken in the lab and there will be further opportunities to learn these structural methods as well as other molecular biological and biochemical techniques.
The post holder should embody and demonstrate the Crick ethos and ways of working: bold, open and collegial. The candidate must be registered at a UK Higher Education Institution, studying in the UK and must have completed a minimum of two years’ undergraduate study in a relevant discipline, and on track to receive a final degree grade of 2:1 or 1. In addition, they should be able demonstrate the following experience and key competencies:
- The project would be suited to a candidate studying for a biochemistry or biophysics degree. An interest in HIV-1 biology or DNA repair would be an advantage.
- Good knowledge in relevant scientific area(s)
- Good written and spoken communication skills
- Ability to work independently and also capable of interacting within a group
1. Morris, E.R., Caswell, S.J., Kunzelmann, S., Arnold, L.H., Purkiss, A.G., Kelly, G. and Taylor, I.A. (2020)
Crystal structures of SAMHD1 inhibitor complexes reveal the mechanism of water-mediated dNTP hydrolysis.
Nature Communications 11: 3165. PubMed abstract
2. Coquel, F., Silva, M.-J., Técher, H., Zadorozhny, K., Sharma, S., Nieminuszczy, J., . . . Pasero, P. (2018)
SAMHD1 acts at stalled replication forks to prevent interferon induction.
Nature 557: 57-61. PubMed abstract