TAILIEUCHUNG - Báo cáo khoa học: Regulation of the muscle-specific AMP-activated protein kinase a2b2c3 complexes by AMP and implications of the mutations in the c3-subunit for the AMP dependence of the enzyme

The AMP-activated protein kinase is an evolutionarily conserved hetero-trimer that is important for metabolic sensing in all eukaryotes. The muscle-specific isoform of the regulatory c-subunit of the kinase, AMP-activated protein kinasec3, has a key role in glucose and fat metabolism in skeletal muscle, as suggested by metabolic characterization of humans, pigs and mice harboring substitutions in the AMP-binding Bateman domains ofc3. | ỊFEBS Journal Regulation of the muscle-specific AMP-activated protein kinase a2p2y3 complexes by AMP and implications of the mutations in the c3-subunit for the AMP dependence of the enzyme Kerstin Lindgren Mattias Ormestad Marten Persson Sofia Martinsson L. Thomas Svensson and Margit Mahlapuu Discovery Research Biovitrum AB Goteborg Sweden Keywords allosteric regulation by AMP AMP-activated protein kinase y3 isoform Correspondence M. Mahlapuu Discovery Research Biovitrum AB Biotech Center Arvid Wallgrens Backe 20 SE-413 46 Goteborg Sweden Fax 46 31 749 1101 Tel 46 31 749 1126 E-mail These authors contributed equally to this study Received 9 February 2007 revised 20 March 2007 accepted 4 April2007 doi The AMP-activated protein kinase is an evolutionarily conserved heterotrimer that is important for metabolic sensing in all eukaryotes. The musclespecific isoform of the regulatory y-subunit of the kinase AMP-activated protein kinase y3 has a key role in glucose and fat metabolism in skeletal muscle as suggested by metabolic characterization of humans pigs and mice harboring substitutions in the AMP-binding Bateman domains of y3. We demonstrate that AMP-activated protein kinase a2p2y3 trimers are allosterically activated approximately three-fold by AMP with a half-maximal stimulation at or pM as measured for complexes expressed in Escherichia coli or mammalian cells respectively. We show that mutations in the N-terminal Bateman domain of y3 R225Q H306R and R307G increased the values for AMP whereas the fold activation of the enzyme by 200 IM AMP remained unchanged in comparison to the wild-type complex. The mutations in the C-terminal Bateman domain of y3 H453R and R454G on the other hand substantially reduced the fold stimulation of the complex by 200 pM AMP and resulted in AMP dependence curves similar to those of the double mutant R225Q R454G. A V224I mutation in y3 known to .

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