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

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 insu...

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Autores principales: Thomas, Elaine C., Hook, Sharon C., Gray, Alexander, Chadt, Alexandra, Carling, David, Al-Hasani, Hadi, Heesom, Kate J., Hardie, D. Grahame, Tavaré, Jeremy M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Portland Press Ltd. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156765/
https://www.ncbi.nlm.nih.gov/pubmed/30135087
http://dx.doi.org/10.1042/BCJ20180475
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author Thomas, Elaine C.
Hook, Sharon C.
Gray, Alexander
Chadt, Alexandra
Carling, David
Al-Hasani, Hadi
Heesom, Kate J.
Hardie, D. Grahame
Tavaré, Jeremy M.
author_facet Thomas, Elaine C.
Hook, Sharon C.
Gray, Alexander
Chadt, Alexandra
Carling, David
Al-Hasani, Hadi
Heesom, Kate J.
Hardie, D. Grahame
Tavaré, Jeremy M.
author_sort Thomas, Elaine C.
collection PubMed
description 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.
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spelling pubmed-61567652018-10-15 Isoform-specific AMPK association with TBC1D1 is reduced by a mutation associated with severe obesity Thomas, Elaine C. Hook, Sharon C. Gray, Alexander Chadt, Alexandra Carling, David Al-Hasani, Hadi Heesom, Kate J. Hardie, D. Grahame Tavaré, Jeremy M. Biochem J Research Articles 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. Portland Press Ltd. 2018-09-28 2018-09-25 /pmc/articles/PMC6156765/ /pubmed/30135087 http://dx.doi.org/10.1042/BCJ20180475 Text en © 2018 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Articles
Thomas, Elaine C.
Hook, Sharon C.
Gray, Alexander
Chadt, Alexandra
Carling, David
Al-Hasani, Hadi
Heesom, Kate J.
Hardie, D. Grahame
Tavaré, Jeremy M.
Isoform-specific AMPK association with TBC1D1 is reduced by a mutation associated with severe obesity
title Isoform-specific AMPK association with TBC1D1 is reduced by a mutation associated with severe obesity
title_full Isoform-specific AMPK association with TBC1D1 is reduced by a mutation associated with severe obesity
title_fullStr Isoform-specific AMPK association with TBC1D1 is reduced by a mutation associated with severe obesity
title_full_unstemmed Isoform-specific AMPK association with TBC1D1 is reduced by a mutation associated with severe obesity
title_short Isoform-specific AMPK association with TBC1D1 is reduced by a mutation associated with severe obesity
title_sort isoform-specific ampk association with tbc1d1 is reduced by a mutation associated with severe obesity
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156765/
https://www.ncbi.nlm.nih.gov/pubmed/30135087
http://dx.doi.org/10.1042/BCJ20180475
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