Structure and subunit composition

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AMPK exists in the cell as a heterotrimeric complex with one catalytic (a, 63 kDa) and two regulatory subunits (b, 30kDa, andg, 38-63 kDa) in a 1a:1b:1g ratio (Figure 1). The a subunit contains a conventional serine/threonine kinase domain at the N-terminus followed by an auto-inhibitory domain, and a C-terminus containing the domains required for binding of b and g subunits (Crute et al., 1998). The b subunit contains two characterized elements, a central domain ensuring the binding of AMPK complexes to glycogen (Hudson et al., 2003; Polekhina et al., 2003) and a C-terminal region acting as a tethering domain for a and g subunits (Iseli et al., 2005; Townley and Shapiro, 2007). The g subunit contains a variable N-terminal region followed by four highly conserved cystathionine-b-synthase (CBS) sequence repeats (small motifs found in tandem pairs termed Bateman domains (Bateman, 1997)), capable of binding adenine nucleotides, such as AMP or ATP (Scott et al., 2004; Townley and Shapiro, 2007; Xiao et al., 2007). Further isoforms have been identified for each of the three AMPK subunits (a1, a2, b1, b2, g1, g2, g3 with splice variants for the g2 and g3 isoforms adding to the diversity), encoded by distinct genes and theoretically leading to formation of at least 12 different complexes. These combinations confer different properties to the AMPK complexes through differences in subcellular localization and signaling functions (Cheung et al., 2000; Salt et al., 1998a). Thus, the tissue-specific subunit composition may be important to determine a specialized cellular and systemic response to different metabolic stresses. Recent investigation of isoform composition of AMPK complexes in human skeletal muscle found that only 3 of the 12 potential AMPK complexes were present (a2b2g1>>a2b2g3=a1b2g1) and were activated differently, depending on exercise intensity and duration (Birk and Wojtaszewski, 2006). AMPKa1 catalytic subunit expression is relatively distributed across adipose tissue, pancreas, lung, spleen and kidney. Skeletal and cardiac muscles predominantly express AMPKa2 catalytic subunit. While the b1 subunit is ubiquitously expressed,  AMPK b2 subunit is abundantly expressed in skeletal muscle and heart. Interestingly, expression of the g3 subunit appears highly specific to glycolytic skeletal muscle whereas g1 and g2 show broad tissue distribution (Cheung et al., 2000).