Stabilization of Protein-Protein Interactions between CaMKK2
and 14-3-3 by Fusicoccins

J 2020

Stabilization of Protein-Protein Interactions between CaMKK2 and 14-3-3 by Fusicoccins

SANTO, Domenico Lentini; Olivia PETRVALSKA; Veronika OBSILOVA; Christian OTTMAN; Tomas OBSIL et al.

Základní údaje

Originální název

Stabilization of Protein-Protein Interactions between CaMKK2 and 14-3-3 by Fusicoccins

Autoři

SANTO, Domenico Lentini; Olivia PETRVALSKA; Veronika OBSILOVA; Christian OTTMAN a Tomas OBSIL

Vydání

ACS Chemical Biology, WASHINGTON, AMER CHEMICAL SOC, 2020, 1554-8929

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10608 Biochemistry and molecular biology

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 5.100

Označené pro přenos do RIV

Ano

Kód RIV

RIV/00216224:90127/20:00139237

Organizační jednotka

CIISB II

Klíčová slova anglicky

CaMKK2; phosphorylation; 14-3-3 protein; ; Fusicoccin A

Štítky

ne MU, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 29. 3. 2025 14:29, Mgr. Eva Dubská

Anotace

V originále

Ca2+/calmodulin-dependent protein kinase kinase 2 (CaMKK2) regulates several key physiological and pathophysiological processes, and its dysregulation has been implicated in obesity, diabetes, and cancer. CaMKK2 is inhibited through phosphorylation in a process involving binding to the scaffolding 14-3-3 protein, which maintains CaMKK2 in the phosphorylation-mediated inhibited state. The previously reported structure of the N-terminal CaMKK2 14-3-3-binding motif bound to 14-3-3 suggested that the interaction between 14-3-3 and CaMKK2 could be stabilized by small-molecule compounds. Thus, we investigated the stabilization of interactions between CaMKK2 and 14-3-3 gamma by Fusicoccin A and other fusicoccanes-diterpene glycosides that bind at the interface between the 14-3-3 ligand binding groove and the 14-3-3 binding motif of the client protein. Our data reveal that two of five tested fusicoccanes considerably increase the binding of phosphopeptide representing the 14-3-3 binding motif of CaMKK2 to 14-3-3 gamma. Crystal structures of two ternary complexes suggest that the steric contacts between the C-terminal part of the CaMKK2 14-3-3 binding motif and the adjacent fusicoccane molecule are responsible for differences in stabilization potency between the study compounds. Moreover, our data also show that fusicoccanes enhance the binding affinity of phosphorylated full-length CaMKK2 to 14-3-3 gamma, which in turn slows down CaMKK2 dephosphorylation, thus keeping this protein in its phosphorylation-mediated inhibited state. Therefore, targeting the fusicoccin binding cavity of 14-3-3 by small-molecule compounds may offer an alternative strategy to suppress CaMKK2 activity by stabilizing its phosphorylation-mediated inhibited state.

Návaznosti

90127, velká výzkumná infrastruktura

Název: CIISB II

Citovat

SANTO, Domenico Lentini; Olivia PETRVALSKA; Veronika OBSILOVA; Christian OTTMAN a Tomas OBSIL. Stabilization of Protein-Protein Interactions between CaMKK2 and 14-3-3 by Fusicoccins. ACS Chemical Biology. WASHINGTON: AMER CHEMICAL SOC, 2020, roč. 15, č. 11, s. 3060-3071. ISSN 1554-8929. Dostupné z: https://doi.org/10.1021/acschembio.0c00821.

@article{2487419,
   author = {Santo, Domenico Lentini and Petrvalska, Olivia and Obsilova, Veronika and Ottman, Christian and Obsil, Tomas},
   article_location = {WASHINGTON},
   article_number = {11},
   doi = {https://doi.org/10.1021/acschembio.0c00821},
   keywords = {CaMKK2; phosphorylation; 14-3-3 protein; ; Fusicoccin A},
   language = {eng},
   issn = {1554-8929},
   journal = {ACS Chemical Biology},
   title = {Stabilization of Protein-Protein Interactions between CaMKK2 and 14-3-3 by Fusicoccins},
   url = {https://pubs.acs.org/doi/10.1021/acschembio.0c00821},
   volume = {15},
   year = {2020}
}

TY  - JOUR
ID  - 2487419
AU  - Santo, Domenico Lentini - Petrvalska, Olivia - Obsilova, Veronika - Ottman, Christian - Obsil, Tomas
PY  - 2020
TI  - Stabilization of Protein-Protein Interactions between CaMKK2 and 14-3-3 by Fusicoccins
JF  - ACS Chemical Biology
VL  - 15
IS  - 11
SP  - 3060-3071
EP  - 3060-3071
PB  - AMER CHEMICAL SOC
SN  - 15548929
KW  - CaMKK2
KW  - phosphorylation
KW  - 14-3-3 protein
KW  -
KW  - Fusicoccin A
UR  - https://pubs.acs.org/doi/10.1021/acschembio.0c00821
N2  - Ca2+/calmodulin-dependent protein kinase kinase 2 (CaMKK2) regulates several key physiological and pathophysiological processes, and its dysregulation has been implicated in obesity, diabetes, and cancer. CaMKK2 is inhibited through phosphorylation in a process involving binding to the scaffolding 14-3-3 protein, which maintains CaMKK2 in the phosphorylation-mediated inhibited state. The previously reported structure of the N-terminal CaMKK2 14-3-3-binding motif bound to 14-3-3 suggested that the interaction between 14-3-3 and CaMKK2 could be stabilized by small-molecule compounds. Thus, we investigated the stabilization of interactions between CaMKK2 and 14-3-3 gamma by Fusicoccin A and other fusicoccanes-diterpene glycosides that bind at the interface between the 14-3-3 ligand binding groove and the 14-3-3 binding motif of the client protein. Our data reveal that two of five tested fusicoccanes considerably increase the binding of phosphopeptide representing the 14-3-3 binding motif of CaMKK2 to 14-3-3 gamma. Crystal structures of two ternary complexes suggest that the steric contacts between the C-terminal part of the CaMKK2 14-3-3 binding motif and the adjacent fusicoccane molecule are responsible for differences in stabilization potency between the study compounds. Moreover, our data also show that fusicoccanes enhance the binding affinity of phosphorylated full-length CaMKK2 to 14-3-3 gamma, which in turn slows down CaMKK2 dephosphorylation, thus keeping this protein in its phosphorylation-mediated inhibited state. Therefore, targeting the fusicoccin binding cavity of 14-3-3 by small-molecule compounds may offer an alternative strategy to suppress CaMKK2 activity by stabilizing its phosphorylation-mediated inhibited state.
ER  -

SANTO, Domenico Lentini; Olivia PETRVALSKA; Veronika OBSILOVA; Christian OTTMAN a Tomas OBSIL. Stabilization of Protein-Protein Interactions between CaMKK2 and 14-3-3 by Fusicoccins. \textit{ACS Chemical Biology}. WASHINGTON: AMER CHEMICAL SOC, 2020, roč.~15, č.~11, s.~3060-3071. ISSN~1554-8929. Dostupné z: https://doi.org/10.1021/acschembio.0c00821.

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