Post-translational regulation of AMPK

Research Opportunity
PhD, Masters by Research, Honours, Master of Biomedical Science
Project Status
Future
Department
Medicine and Radiology
Location
St Vincent's Hospital
Supervisor Email Number Webpage
Prof Bruce Kemp Personal web page

Project Details

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

Cardiometabolic



Research Opportunities

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

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Key Contact

For further information about this research, please contact a supervisor.

Department

Medicine and Radiology

Research Node

St Vincent's Hospital