Autoregulation of AMPK complexes

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AMPK, like other protein kinases, autoregulates its own activity through structural elements, that directly block its catalytic site. Within the catalytic a subunit, a region that is C-terminal to the kinase domain appears to act as an auto-inhibitory domain (AID) by interfering with kinase substrate binding and catalytic function (Crute et al., 1998). Detailed mutagenesis studies provide evidence that a conserved short segment of the a subunit [a1-(313-335)], forming an a helix, binds to the kinase domain in an inactive conformation and is responsible for auto-inhibition (Pang et al., 2007). Furthermore, three-dimensional structural studies revealed that hydrophobic contacts between the kinase domain and the AID have a predominant role in the allosteric control by AMP (Chen et al., 2009a). Upon binding of AMP, conformational change between low and high activity forms of AMPK alters the interaction between AID and kinase domains and eventually removes the effect of AID on kinase activation and also Thr172 dephosphorylation (Chen et al., 2009a). This mechanism of AMPK inhibition highlights the potential to develop small compounds that activate AMPK by antagonizing the auto-inhibitory role of AID (Pang et al., 2008). In addition to the AID, it has been suggested that AMPK is also inhibited by an internal auto-inhibitory sequence similar to the consensus recognition motif for AMPK substrates but lacking a phosphoryl-able amino acid. Scott and coworkers proposed that, in the absence of AMP, a pseudo-substrate sequence, within the g2 CBS2 sub-domain, binds to the catalytic groove of AMPKa, preventing phosphorylation by the upstream kinase and therefore, access to downstream targets (Scott et al., 2007). When AMP binds to the g subunit, a conformational change prevents the interaction of the pseudo-substrate sequence with the kinase domain and thus, causes activation of AMPK.