Inside each of our thirty trillion cells, a vast number of moving molecular machines collaborate to maintain our health. The crowded cell interior requires quality control mechanisms to ensure correct spatial and temporal protein composition (proteostasis). Small, glutamine-rich, tetratricopeptide repeat protein alpha (SGTA) is a critical player in proteostasis. Its tweezer-like form is thought to grab hydrophobic proteins, shield them from the aqueous cytoplasm, and direct them towards an optimal fate: membrane insertion, refolding by chaperones or degradation by the ubiquitin proteasome pathway. Defects in SGTA function lead to protein aggregation and related diseases such as neurodegeneration, cancer, diabetes and viral infections.
Using a suite of established reagents, this project takes interdisciplinary approaches to decipher SGTA mechanisms, understand its collaborations with other cellular machinery which facilitate quality control, and link these to disease with a view to precision medicine.
The student will gain interdisciplinary technical expertise, tailored towards their interests. The Isaacson lab utilises biochemistry, biophysics and structural biology techniques while the Eggert lab specialises in cell biology, lipidomics and chemical biology.
Example PhD path:
The first 6 months will entail training in protein expression and purification (Isaacson) to optimise production of recombinant complexes of SGTA and client proteins – a 3-month MRes project would be equivalent but with a single target. Between 6 and 18 months they will receive cryo-EM training for structural analysis of these complexes and cell biology/lipid/membrane assays (Eggert) to probe SGTA complex function, including membrane insertion. This will allow the student to obtain initial results and their own data in time for upgrade. To establish competence in the techniques the student will initially receive in person guidance for 100% of their laboratory time which will be decreased gradually. After 18 months the student will continue to receive support and guidance with particular emphasis on experimental design and interpretation, dividing their time between Isaacson/Eggert labs depending on results and project directions which will be constantly monitored through lab meetings/individual progress reporting. Additional training, e.g. other structural techniques, lipid mass spectrometry and associated computational analyses will be provided as needed. The object is to provide sufficient room so that the student can benefit from guiding their own PhD but to provide ongoing support. Throughout the PhD and especially at the start of the final year we will formulate a plan for the thesis and remaining experimental work; we will reserve the last four months for thesis writing.
