Sweet transfer in cholesterol homeostasis: molecular details of glycosylation of Low-Density-Lipoprotein-Receptors (ANGULO_U19DTP)
- Research Area Bioscience for Health
- Partner The University of East Anglia (UEA)
Dr Jesus Angulo -
- Application Deadline 26/11/2018
Glycosylation is one of the most important post-translational modification of proteins, whereby sugar residues are transferred to specific amino acids of proteins, by the action of glycosyltransferases (GTs), providing a variety of different structural and functional roles to the resulting glycoprotein. Among GTs, GalNAc-transferases are very important in protein signalling and endocytic receptor biology. However, due to the difficulties in crystallisation of their complexes, little is known on the molecular aspects of GalNAc-Ts and their role in fine tuning protein-protein interactions.
In this project, we seek to unveil the structural features at atomic detail of the action of GalNAc-T11, an enzyme that specifically glycosylates LDLR and LDLR-like receptors, fine-tuning the regulation of LDL (and hence, cholesterol homeostasis) and the reabsorption of other molecules in the kidney. Recent work has revealed that the “sweet tag” (GalNAc) transferred to the receptor by GalNAc-T11 is important for its interaction with LDL and in turn for an increased uptaking of LDL by LDLR. GalNAc-T11 is unique because it only recognises folded domains within LDLR and does not glycosylate the acceptor sites when these domains are unstructured. To that aim we will use NMR spectroscopy, molecular modelling (docking, long molecular dynamics) and other biophysical techniques (cell-based screening).
The project is an excellent opportunity for first class training of a student in a multidisciplinary environment. The student will be trained in advanced NMR spectroscopy, modelling, recombinant protein production, and cell-based inhibition assays. UEA and NRP provide also training in research techniques, data handling, and transferable skills in paper and grant writing and presentation skills.