beta-subunit myristoylation functions as an energy sensor by modulating the dynamics of AMP-activated Protein Kinase
AuthorAli, N; Ling, N; Krishnamurthy, S; Oakhill, JS; Scott, JW; Stapleton, DI; Kemp, BE; Anand, GS; Gooley, PR
Source TitleScientific Reports
PublisherNATURE PUBLISHING GROUP
AffiliationBiochemistry and Pharmacology
Medicine (St Vincent's)
Document TypeJournal Article
CitationsAli, N., Ling, N., Krishnamurthy, S., Oakhill, J. S., Scott, J. W., Stapleton, D. I., Kemp, B. E., Anand, G. S. & Gooley, P. R. (2016). beta-subunit myristoylation functions as an energy sensor by modulating the dynamics of AMP-activated Protein Kinase. SCIENTIFIC REPORTS, 6 (1), https://doi.org/10.1038/srep39417.
Access StatusOpen Access
The heterotrimeric AMP-activated protein kinase (AMPK), consisting of α, β and γ subunits, is a stress-sensing enzyme that is activated by phosphorylation of its activation loop in response to increases in cellular AMP. N-terminal myristoylation of the β-subunit has been shown to suppress Thr172 phosphorylation, keeping AMPK in an inactive state. Here we use amide hydrogen-deuterium exchange mass spectrometry (HDX-MS) to investigate the structural and dynamic properties of the mammalian myristoylated and non-myristoylated inactivated AMPK (D139A) in the presence and absence of nucleotides. HDX MS data suggests that the myristoyl group binds near the first helix of the C-terminal lobe of the kinase domain similar to other kinases. Our data, however, also shows that ATP.Mg2+ results in a global stabilization of myristoylated, but not non-myristoylated AMPK, and most notably for peptides of the activation loop of the α-kinase domain, the autoinhibitory sequence (AIS) and the βCBM. AMP does not have that effect and HDX measurements for myristoylated and non-myristoylated AMPK in the presence of AMP are similar. These differences in dynamics may account for a reduced basal rate of phosphorylation of Thr172 in myristoylated AMPK in skeletal muscle where endogenous ATP concentrations are very high.
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