Intrasteric control of AMPK via the  1 subunit AMP allosteric regulatory site

摘要: AMP-activated protein kinase (AMPK) is a alphabetagamma heterotrimer that activated in response to both hormones and intracellular metabolic stress signals. AMPK regulated by phosphorylation on the alpha subunit AMP allosteric control previously thought be mediated gamma subunits. Here we present evidence adjacent pairs of CBS repeat sequences (after Cystathionine Beta Synthase) form an binding site related to, but distinct from classical phosphorylase, can also bind ATP. The gamma(1) CBS1/CBS2 pair, modeled structures inosine monophosphate dehydrogenase crystal structure, contains three arginine residues 70, 152, 171 His151. yeast homolog, snf4 His151Gly substitution, when this introduced into gamma(1), substantially lost explains why snf1p/snf4p complex insensitive AMP. Arg70 corresponds mutation human gamma(2) pig gamma(3) genes identified cause unusual cardiac phenotype glycogen storage disease, respectively. Mutation any Arg Gln abolishes expressed holoenzyme. Arg/Gln mutations suppress described inhibitory properties ATP render enzyme constitutively active. We propose acts as intrasteric inhibitor bridging subunits functions derepress activity.