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Abstract
AMP-activated protein kinase (AMPK) is a key regulator of cellular and systemic energy homeostasis which achieves this through the phosphorylation of a myriad of downstream targets. One target is TBC1D1 a Rab-GTPase-activating protein that regulates glucose uptake in muscle cells by integrating insulin signalling with that promoted by muscle contraction. Ser 237 in TBC1D1 is a target for phosphorylation by AMPK, an event which may be important in regulating glucose uptake. Here, we show AMPK heterotrimers containing the α1, but not the α2, isoform of the catalytic subunit form an unusual and stable association with TBC1D1, but not its paralogue AS160. The interaction between the two proteins is direct, involves a dual interaction mechanism employing both phosphotyrosine-binding (PTB) domains of TBC1D1 and is increased by two different pharmacological activators of AMPK (AICAR and A769962). The interaction enhances the efficiency by which AMPK phosphorylates TBC1D1 on its key regulatory site, Ser 237. Furthermore, the interaction is reduced by a naturally occurring R125W mutation in the PTB1 domain of TBC1D1, previously found to be associated with severe familial obesity in females, with a concomitant reduction in Ser 237 phosphorylation. Our observations provide evidence for a functional difference between AMPK α-subunits and extend the repertoire of protein kinases that interact with substrates via stabilisation mechanisms that modify the efficacy of substrate phosphorylation.
Original language | English |
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Pages (from-to) | 2969-2983 |
Number of pages | 35 |
Journal | The Biochemical journal |
Volume | 475 |
Issue number | 18 |
Early online date | 22 Aug 2018 |
DOIs | |
Publication status | Published - 25 Sept 2018 |
ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Cell Biology
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Dive into the research topics of 'Isoform-specific AMPK association with TBC1D1 is reduced by a mutation associated with severe obesity'. Together they form a unique fingerprint.Projects
- 1 Finished
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Role of AMPK in Nutrient Sensing and in Cancer (Investigator Award Renewal)
Hardie, G. (Investigator)
1/10/17 → 31/03/24
Project: Research
Profiles
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Gray, Alexander
- Leverhulme Research Centre for Forensic Science - Principal Investigator
Person: Research