4 Year Wellcome Trust PhD Programme: The mechanism of cellular glucose sensing: architecture of “super-complexes” formed by LKB1 and AMPK

AMP-activated protein kinase (AMPK) is a cellular energy sensor and a key target for development of drugs aimed at both diabetes and cancer [Hardie (2017) Science 357:455; Hardie (2017) Cancer Cell 31:163; Lin & Hardie (2017) Cell Metabolism, in press]. We have recently reported that AMPK can also sense the availability of glucose; upon glucose deprivation, it assembles into a “super-complex” at the lysosomal surface involving the v-ATPase, p18/Lamtor1, Axin, LKB1 and AMPK [Zhang et al (2017) Nature 548:112]. The long-term aim of the project is to define the architecture of this super-complex via various approaches:
1) immunoprecipitation of tagged p18/Lamtor1 to identify, using mass spectrometry, novel proteins that may be associated with the super-complex;
2) use of molecular biology to map interacting domains within the complex;
3) generation of sub-complexes that might be suitable for structural analysis, e.g. by cryo-EM;
4) use of cell biological approaches to confirm location of components of the complex at the lysosome.