Understanding how cytosolic kinases regulate T-cell receptor signalling using multi-scale simulations

Project Details

The main aim of this project is to use multi-scale molecular dynamics simulations to understand how cytosolic kinases regulate the T-cell receptor (TCR) signaling.

The T-cell receptor is a multisubunit transmembrane protein located in T-lymphocytes. It is critical for the survival and function of T-cells and for the immune response, as it initiates various biological processes responsible for the protection of the organism from infectious agents. TCR activation is initiated by interactions of the TCR with antigenic peptides complexed to Major Histocompatibility Complex (MHC) molecules. MHC/peptide binding stimulates the phosphorylation of the cytosolic region of the TCR by cytosolic kinases initiating multiple signaling cascades. Despite many functional data about the TCR activation and signaling, the exact process by which the ligation of TCR is translated into signal remains elusive. Further knowledge about the phosphorylation propagation process by cytosolic kinases is required to allow us to understand the various signals induced by the TCR complex.

Molecular simulations can provide a ‘computational microscope’ enabling us to probe the mechanistic details of the activation of signaling receptors at the molecular level. Our recent work demonstrated that computational tools can be used to investigate in detail the molecular mechanisms and the energetics by which cytosolic proteins activate signaling receptors. In this project, the student will use molecular dynamics simulations and molecular modelling to provide novel insight into: i) the molecular and mechanistic details of the localization of different kinases that are involved in TCR signaling to model membranes, ii) how these kinases are activated, iii) the dynamic interactions between kinases and the TCR cytosolic regions. These results, combined with experimental data from our collaborators at the University of Oxford, will fill an important gap in our understanding of TCR signaling.

Environment:

The student will be based in the University of Leeds in the Infection and Immunity Section, Leeds Institute of Cancer and Pathology, University of Leeds. Training will be provided in the relevant technical areas. For more information about the group visit our webpage at: http://medhealth.leeds.ac.uk/info/983/infection_and_immunity/2345/computational_biophysics_of_membrane_proteins

Eligibility

You should hold a first degree equivalent to at least a UK upper second class honours degree in a relevant subject. The project would suit a student with background in biochemistry, chemistry, physics, engineering or computer sciences.

Candidate whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study, the Faculty minimum requirements are:

• British Council IELTS - score of 6.5 overall, with no element less than 6.0
• TOEFL iBT - overall score of 92 with the listening and reading element no less than 21, writing element no less than 22 and the speaking element no less than 23.

How to Apply

To apply for this scholarship applicants should complete a Faculty Scholarship Application form using the link below http://medhealth.leeds.ac.uk/download/3551/fmh_scholarship_application_2017_18 and send this alongside a full academic CV, degree certificates and transcripts (or marks so far if still studying) to the Faculty Graduate School [Email Address Removed]

We also require 2 academic references to support your application. Please ask your referees to send these references on your behalf, directly to [Email Address Removed]

If you have already applied for other projects using the Faculty Scholarship Application form you do not need to complete this form again. Instead you should email [Email Address Removed] to inform us you would like to be considered for this scholarship project.

Any queries regarding the application process should be directed to [Email Address Removed]

To discuss the project informally please contact Dr Antreas Kalli ([Email Address Removed]) with a copy of your CV.