Postgraduate research opportunities

Is there a universal mechanism for biological ammonium transport

The vision of this PhD project is to establish whether there is a universal mechanism for biological ammonium transport. Beyond the elucidation of a central biological process, this work will have important medical implications, offering a mechanistic explanation to correlate Rh malfunction and associated diseases and

Number of places

1

Opens

14 February 2020

Deadline

31 March 2021

Duration

36 Months

Eligibility

B.Sc. in a Biological Science at Upper Second Class or above.

Project Details

Context of the research: Ammonium is a vital source of nitrogen for bacteria, fungi and plants and a toxic metabolic waste product for animals. Hence, ammonium transport across biological membranes is a process of fundamental importance in all living organisms and is accomplished by the ubiquitous Amt/Mep/Rh superfamily of membrane proteins. The physiological importance of this family of protein is underlined by the role of particular Mep proteins in yeast filamentation, a dimorphic transition often related to the virulence of pathogenic yeast. Rh mutations are associated with numerous human pathologies including anaemia, blood acidosis and potentially cancer. An improved understanding of the function of ammonium transporters therefore has important medical implications alongside the elucidation of a central biological process.

 

Aim and objectives: A plethora of functional and structural studies aimed at elucidating the mechanism of ammonium transport by the Amt/Mep/Rh proteins has led to considerable controversy(1)(1) and the exact mechanism of ammonium transport by these proteins remains largely elusive and controversial. The vision of this PhD is to establish whether there is a universal mechanism for biological ammonium transport and understand the impact of Amt/Mep/Rh activity on fungal pathogenicity and Human physiopathology.

Potential applications and benefits: This project is transformative as the results obtained will represent a real breakthrough in the Amt/Rh field, elucidating the long standing controversial mechanism of conduction of ammonium by this important family of transporters. This work has the potential for significant impact on society, both socially and economically, given the importance of the proteins in different biological processes. It will also have important medical implications, providing important clues to design new drugs or therapies effective against fungal pathogens. This is extremely timely: a million people die every year from fungal infections and fungi destroy a third of all food crops each year, which would be sufficient to feed 600 million people(2)(2). This work will also offer a mechanistic explanation of how Rh malfunction cause diseases, particularly anaemia and blood acidosis.

 Techniques used:

 1- Purification of EcAmtB (E. coli C43 cells), human Rhesus (HEK-293 cells) and fungal Mep (S. cerevisiae cells) proteins/reconstitution into liposomes and nanodisc.

2- Functional study using Solid Supported Membrane Electrophysiology (SSME).

3- Advance structural analysis by X-ray crystallography using the newly developed Pan-Dataset Density Analysis methods and single wavelength anomalous diffraction studies.

4- Structural study using Cryogenic Electron Microscopy of the proteins reconstituted in nanodisc.

5- Simulation of proton transfer using quantum mechanics and empirical valence bond calculations.

6- Yeast filamentation test

Funding Details

Applicant will need to self-fund, find sponsorship for tuition and bench fees of £10,000 per annum for duration of studies

Supervisor

Primary Supervisor: Dr. Arnaud Javelle

Email: Arnaud.javelle@strath.ac.uk

 

Secondary Supervisor: Prof. Paul Hoskisson

Email: paul.hoskisson@strath.ac.uk

Contact us

Primary Supervisor: Dr. Arnaud Javelle

Email: Arnaud.javelle@strath.ac.uk