“Our research is aimed at understanding the regulation of energy metabolism”
AMP-activated protein kinase (AMPK) responds to depletion in the intracellular concentration of ATP. AMPK is activated by phosphorylation, and binding of ADP to the g subunit prevents dephosphorylation of the activated phospho-form of the complex. Once activated, AMPK phosphorylates a number of downstream targets switching-on catabolic pathways, and switching-off anabolic pathways. Recent studies have shown that AMPK plays a role in the regulation of whole body energy metabolism, including the control of feeding. Using transgenic models we have shown that deletion of AMPK in the hypothalamus leads to an obese phenotype.
Phosphorylation and activation of AMPK is catalysed by either LKB1 or Ca2+/calmodulin dependent protein kinase kinase b. CaMKKb is highly expressed in neuronal tissues and is implicated in hippocampal function. Inactivating mutations within LKB1 lead to a rare, dominantly inherited cancer predispostion in humans, termed Peutz-Jeghers Syndrome. Collectively, these findings suggest that AMPK may play a role in human diseases characterized by defects in energy metabolism. Our current focus is to understand the regulation of AMPK using structure/function analyses and the physiological role of AMPK using transgenic models.
Structure of AMPK bound to a small molecule activator.
Xiao, B., Sanders, M. J., Carmena, D., Bright, N. J., Haire, L. F., Underwood, E., Patel, B. R., Heath, R. B., Walker, P. A., Hallen, S., Giordanetto, F., Martin, S. R., Carling, D., & Gamblin, S. J. (2013). Structural basis of AMPK regulation by small molecule activators. Nature Communications, 4.
Mayer, F. V., Heath, R., Underwood, E., Sanders, M. J., Carmena, D., McCartney, R. R., Leiper, F. C., Xiao, B., Jing, C., Walker, P. A., Haire, L. F., Ogrodowicz, R., Martin, S. R., Schmidt, M. C., Gamblin, S. J., & Carling, D. (2011). ADP regulates SNF1, the saccharomyces cerevisiae homolog of AMP-activated protein kinase. Cell Metabolism, 14(5), 707–714.
Xiao, B., Sanders, M. J., Underwood, E., Heath, R., Mayer, F. V., Carmena, D., Jing, C., Walker, P. A., Eccleston, J. F., Haire, L. F., Saiu, P., Howell, S. A., Aasland, R., Martin, S. R., Carling, D., & Gamblin, S. J. (2011). Structure of mammalian AMPK and its regulation by ADP. Nature, 472, 230–233.
Thornton, C., Bright, N. J., Sastre, M., Muckett, P. J., & Carling, D. (2011). AMP-activated protein kinase (AMPK) is a tau kinase, activated in response to amyloid-peptide exposure. The Biochemical Journal, 434(3), 503–512.
Woods, A., Heslegrave, A., Muckett, P. J., Levene, A., Clements, M., Mobberley, M., Ryder, T. A., Abu-Hayyeh, S., Williamson, C., Goldin, R. D., Ashworth, A., Withers, D. J., & Carling, D. (2010). LKB1 is required for hepatic bile acid transport and canalicular membrane integrity in mice. The Biochemical Journal.