Citation

BibTex format

@article{Chen:2026:10.1042/BCJ20250342,
author = {Chen, S-Y and Bennett, J and Navaratnam, N and Fiadeiro, R and Woods, A and Montoya, A and Shliaha, PV and Kunzelmann, S and Howell, SA and Mehmood, S and Purkiss, AG and Wilson, JR and Gamblin, SJ and Carling, D},
doi = {10.1042/BCJ20250342},
journal = {Biochem J},
pages = {621--637},
title = {Binding of 14-3-3 stabilises recombinant AMPKγ2-containing complexes.},
url = {http://dx.doi.org/10.1042/BCJ20250342},
volume = {483},
year = {2026}
}
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TY  - JOUR
AB  - AMP-activated protein kinase (AMPK) plays an important role in maintaining energy homeostasis in mammals. AMPK is a heterotrimer of an α catalytic subunit and two regulatory subunits, β and γ. In mammals, each subunit has different isoforms (α1/α2, β1/ β2, and γ1/γ2/γ3) encoded by separate genes, leading to the potential expression of 12 AMPK complexes. Here, we show that AMPK containing the long forms of γ2 (γ2a, encoding a protein of 569 amino acids, and γ2c, 525 amino acids) binds to 14-3-3. In contrast to AMPK containing the short form of γ2 (γ2b, 328 amino acids), bacterial expression of AMPK containing the long forms of γ2 requires co-expression with 14-3-3 and prior phosphorylation of Thr172 within the α subunit. AMPKγ2-14-3-3 complexes have reduced activity compared with AMPKγ1 or AMPKγ2b but retain allosteric activation by AMP and the AMPK activator, 991. We found that two predicted 14-3-3 binding sites within γ2a (T97 and S122) were phosphorylated in the bacterially expressed AMPK complex. Furthermore, we show that a peptide spanning these two phosphorylated sites binds to 14-3-3 in vitro and determined the crystal structure of this 14-3-3-peptide co-complex. These results indicate that 14-3-3 binds to the N-terminal region of γ2a/c, reducing the activity of AMPK relative to AMPKγ1 and AMPKγ2b. Our findings reveal a new mode of regulation of AMPK containing the long forms of γ2. While the biological significance of 14-3-3 binding to AMPKγ2a/c complexes remains to be determined, our studies provide the starting point to begin to address this issue.
AU  - Chen,S-Y
AU  - Bennett,J
AU  - Navaratnam,N
AU  - Fiadeiro,R
AU  - Woods,A
AU  - Montoya,A
AU  - Shliaha,PV
AU  - Kunzelmann,S
AU  - Howell,SA
AU  - Mehmood,S
AU  - Purkiss,AG
AU  - Wilson,JR
AU  - Gamblin,SJ
AU  - Carling,D
DO  - 10.1042/BCJ20250342
EP  - 637
PY  - 2026///
SP  - 621
TI  - Binding of 14-3-3 stabilises recombinant AMPKγ2-containing complexes.
T2  - Biochem J
UR  - http://dx.doi.org/10.1042/BCJ20250342
UR  - https://www.ncbi.nlm.nih.gov/pubmed/41873906
VL  - 483
ER  -
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