Isoform-specific AMPK association with TBC1D1 is reduced by a mutation associated with severe obesity

Author:

Thomas Elaine C.1ORCID,Hook Sharon C.1,Gray Alexander2,Chadt Alexandra34,Carling David5,Al-Hasani Hadi34,Heesom Kate J.1,Hardie D. Grahame2,Tavaré Jeremy M.1

Affiliation:

1. School of Biochemistry, Biomedical Sciences Building, University of Bristol, Bristol, U.K.

2. Division of Cell Signalling & Immunology, School of Life Sciences, University of Dundee, Dundee, U.K.

3. German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich-Heine-University, Medical Faculty, Düsseldorf, Germany

4. German Center for Diabetes Research (DZD), Düsseldorf, Germany

5. Cellular Stress Group, Medical Research Council London Institute of Medical Sciences, Hammersmith Hospital, Imperial College, London, U.K.

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. Ser237 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, Ser237. 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 Ser237 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.

Publisher

Portland Press Ltd.

Subject

Cell Biology,Molecular Biology,Biochemistry

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