Post-translational regulation of AMPK
- Research Opportunity
- PhD, Masters by Research, Honours, Master of Biomedical Science
- Project Status
- Medicine and Radiology
- St Vincent's Hospital
|Prof Bruce Kemp||Personal web page|
We have shown that AMP and direct activating drugs (A-769662) operate synergistically to allosterically activate unphosphorylated AMPK >1000-fold, whereas on their own they have minimal effect. This reversed a 30 year-old dogma in the field and raises the enormous potential for combinatorial therapies involving metformin and novel AMPK drugs. This project will aim to provide a structural and cell-signaling basis to these initial, exciting findings. We recently found that AMPK sensitivity to drugs is entirely dependent on phosphorylation the β-subunit Ser108. This represents a novel paradigm to exploit AMPK as a therapeutic target.
The project will aim to uncover non-canonical cellular mechanisms leading to phosphorylation of Ser108 thereby increasing AMPK drug potency. AMPK activation by upstream kinases CaMKKβ or LKB1 is stimulated by both AMP and ADP, and requires AMPK to be myristoylated.
This indicates a nucleotide-mediated myristoyl-switch mechanism. The aim of this project is to locate the myristoyl group-binding pocket through structural analyses and characterize how the myristoyl group is relocated in response to nucleotide binding.
AMPK regulation in vivo: We have generated knock-in mice with mutations of single amino acids that have been identified in vitro to be important AMPK regulation sites. We have projects available that will aim to characterize the metabolic phenotype of these knock-in mice, including in-depth analysis of any potential effects on insulin sensitivity and whole-body energy metabolism.
This project is conducted in St Vincent’s Institute of Medical Research, Protein Chemistry and Metabolism Unit.
School Research Themes
PhD, Masters by Research, Honours, Master of Biomedical Science Graduate Research Students who are interested in joining this project will need to consider their elegibility as well as other Graduate Research requirements before contacting the supervisor of this research
For further information about this research, please contact a supervisor.