About the Project
Unfortunately, many people carry a DNA mutation inducing a small defect in one of the thousands glycoproteins UGGT surveys. In these individuals, UGGT’s overzealous quality control causes the defective glycoprotein to be retained in the cell and eventually degraded, even if the defect is small and the patient would profit from the residual activity the mutant glycoprotein still carries. Terrible disease ensues. Indeed, retention of glycoprotein mutants cause a broad spectrum of rare diseases. Although each of these life-threatening disorders affects less than 5 out of 10,000 individuals, there are approximately 2,000 known glycoprotein related congenital rare diseases in the medical literature. The size of the pharmaceutical market for each rare disease is small, and this has discouraged investment in this area.
We propose that drugs modulating UGGT activity could rescue secretion of these slightly defective and yet active glycoproteins, by loosening the enzyme’s strict quality control, and allowing the mutant to carry its residual activity to its target destination [see Tax G. et al., Modulation of ERQC and ERAD: a broad-spectrum spanner in the works of cancer cells?, accepted for publication in Journal of Oncology, 2019]. Unfortunately, glycoprotein mis-fold recognition by UGGT remains a mystery. It is not understood how this unique checkpoint enzyme can act on such a wide variety of mis-folded glycoproteins sizes and folds. No UGGT inhibitors are known either.
The project seeks answers the two major questions left unanswered for decades in the field of Eukaryotic secretion and glycoprotein folding: i) how does UGGT, the ERQC checkpoint enzyme, bind its ER partner proteins? and ii) how does UGGT recognise its misfolded substrate glycoproteins? Answers to these questions will be of great value in the development of drugs modulating UGGT activity, for broad-spectrum rescue-of-secretion of responsive mutants in rare disease.
The host laboratory has carried out a high-throughput structure-based lead discovery screen at the XChem laboratory of the Diamond Light Source in Harwell, UK, and discovered a fragment with Kd=600 µM for HsUGGT1. Medicinal chemistry is under way towards developing this molecule into a UGGT modulator. A separate RNA display screen has also selected a 14-aminoacids peptide that binds UGGT. Last but not least, fluorescence microscopy rescue-of-secretion experiments in the host laboratory are monitoring misfolded glycoproteins as they traverse the secretory pathway of wild-type and UGGT knock-out cells. Starting from these preliminary data, the student will contribute to elucidation of the molecular details underpinning UGGT:substrate glycoprotein recognition and of the UGGT:ER partner protein:protein interactions. The outcomes of the study will eventually inform development of novel ways of modulating UGGT function.
UK/EU applicants only.
Applicants are required to hold/or expect to obtain a UK Bachelor Degree 2:1 or better in a relevant subject.
The University of Leicester English language requirements apply where applicable: https://le.ac.uk/study/research-degrees/entry-reqs/eng-lang-reqs/ielts-65
How to apply:
To apply for the PhD please refer to the guidelines and use the application link at https://le.ac.uk/study/research-degrees/funded-opportunities/bbsrc-mibtp
Please also submit your MIBTP notification form at https://warwick.ac.uk/fac/cross_fac/mibtp/pgstudy/phd_opportunities/application/
Project / Funding Enquiries: [Email Address Removed]
Application enquiries to [Email Address Removed]
UK/EU fees and stipend at UKRI rates. For 2020 this will be £15,285 pa
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