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

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985823%3A_____%2F20%3A00535685" target="_blank" >RIV/67985823:_____/20:00535685 - isvavai.cz</a>

Alternative codes found

RIV/00216208:11310/20:10420687

Result on the web

<a href="https://doi.org/10.1021/acschembio.0c00821" target="_blank" >https://doi.org/10.1021/acschembio.0c00821</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acschembio.0c00821" target="_blank" >10.1021/acschembio.0c00821</a>

Result language

angličtina

Original language name

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

Original language description

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 14–3–3γ 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 14–3–3γ. 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 14–3–3γ, 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.

Czech name

—

Czech description

—

Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

10608 - Biochemistry and molecular biology

Project

<a href="/en/project/GA19-00121S" target="_blank" >GA19-00121S: Molecular basis of the 14-3-3 protein-dependent regulation of protein kinase activity</a><br>

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2020

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

ACS Chemical Biology

ISSN

1554-8929

e-ISSN

1554-8937

Volume of the periodical

15

Issue of the periodical within the volume

11

Country of publishing house

US - UNITED STATES

Number of pages

12

Pages from-to

3060-3071

UT code for WoS article

000592981100024

EID of the result in the Scopus database

2-s2.0-85096508476