Multi-Site Modification and Activity Regulation of AMPK in the Complex Context of Exercise——Analysis Based on Protein Structure Biology

AMP-activated protein kinase(AMPK) exists widely in eukaryotes in the form of heterotrimers, and is considered as an energy sensor of cell and a core metabolic regulator of the body. Studies on the relationship between exercise and AMPK have lasted for decades, and found that: 1) acute exercise rapidly activates AMPK; 2) long-term training improves the activity of AMPK in rest state; 3) long-term training attenuates AMPK response to exercise stress. This suggests that AMPK is sensitive to the exercise context set up in the study. The protein structure of AMPK contains multiple phosphorylation sites, as well as ubiquitination,SUMOylation, acetylation, methylation and oxidation sites, most of covalent modifications of these sites are reversible and combinable. The analysis of structural biology can predict that AMPK protein complex is not only a simple “activated state” and “deactivated state”, and α-Thr172 phosphorylation is not necessarily a biomarker of AMPK enzyme activity. Post-translational modification and allosteric regulation at multiple sites enable AMPK subunits to form different intermediate states. The flexibility of the protein structure enables AMPK to respond to complex physiological situations(including complex exercise situations) with different active forms. Future studies can explore the correspondence between multi-site modification and AMPK activity, so as to further analyze the response mechanism of AMPK to exercise.