29ii
Structure of 14-3-3 epsilon in complex with a peptide derived from AMPK gamma 2
Structural highlights
Disease1433E_HUMAN Distal 17p13.3 microdeletion syndrome;17p13.3 microduplication syndrome;Miller-Dieker syndrome. Function1433E_HUMAN Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner. Publication Abstract from PubMedAMP-activated protein kinase (AMPK) plays an important role in maintaining energy homeostasis in mammals. AMPK is a heterotrimer of an alpha catalytic subunit and two regulatory subunits, beta and gamma. In mammals, each subunit has different isoforms (alpha1/alpha2, beta1/ beta2, and gamma1/gamma2/gamma3) encoded by separate genes, leading to the potential expression of 12 AMPK complexes. Here, we show that AMPK containing the long forms of gamma2 (gamma2a, encoding a protein of 569 amino acids, and gamma2c, 525 amino acids) binds to 14-3-3. In contrast to AMPK containing the short form of gamma2 (gamma2b, 328 amino acids), bacterial expression of AMPK containing the long forms of gamma2 requires co-expression with 14-3-3 and prior phosphorylation of Thr172 within the alpha subunit. AMPKgamma2-14-3-3 complexes have reduced activity compared with AMPKgamma1 or AMPKgamma2b but retain allosteric activation by AMP and the AMPK activator, 991. We found that two predicted 14-3-3 binding sites within gamma2a (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 gamma2a/c, reducing the activity of AMPK relative to AMPKgamma1 and AMPKgamma2b. Our findings reveal a new mode of regulation of AMPK containing the long forms of gamma2. While the biological significance of 14-3-3 binding to AMPKgamma2a/c complexes remains to be determined, our studies provide the starting point to begin to address this issue. Binding of 14-3-3 stabilises recombinant AMPKgamma2-containing complexes.,Chen SY, Bennett J, Navaratnam N, Fiadeiro R, Woods A, Montoya A, Shliaha PV, Kunzelmann S, Howell SA, Mehmood S, Purkiss AG, Wilson JR, Gamblin SJ, Carling D Biochem J. 2026 May 6;483(5):621-637. doi: 10.1042/BCJ20250342. PMID:41873906[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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