14-3-3 protein inhibits CaMKK1 by blocking the kinase active site with its last two C-terminal helices

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985823%3A_____%2F23%3A00576929" target="_blank" >RIV/67985823:_____/23:00576929 - isvavai.cz</a>

Alternative codes found

RIV/00216208:11320/23:10471021 RIV/00216208:11310/23:10471021

Result on the web

<a href="https://doi.org/10.1002/pro.4805" target="_blank" >https://doi.org/10.1002/pro.4805</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1002/pro.4805" target="_blank" >10.1002/pro.4805</a>

Result language

angličtina

Original language name

14-3-3 protein inhibits CaMKK1 by blocking the kinase active site with its last two C-terminal helices

Original language description

Ca2+/CaM-dependent protein kinase kinases 1 and 2 (CaMKK1 and CaMKK2) phosphorylate and enhance the catalytic activity of downstream kinases CaMKI, CaMKIV, and protein kinase B. Accordingly, CaMKK1 and CaMKK2 regulate key physiological and pathological processes, such as tumorigenesis, neuronal morphogenesis, synaptic plasticity, transcription factor activation, and cellular energy homeostasis, and promote cell survival. Both CaMKKs are partly inhibited by phosphorylation, which in turn triggers adaptor and scaffolding protein 14-3-3 binding. However, 14-3-3 binding only significantly affects CaMKK1 function. CaMKK2 activity remains almost unchanged after complex formation for reasons still unclear. Here, we aim at structurally characterizing CaMKK1:14-3-3 and CaMKK2:14-3-3 complexes by SAXS, H/D exchange coupled to MS, and fluorescence spectroscopy. The results revealed that complex formation suppresses the interaction of both phosphorylated CaMKKs with Ca2+/CaM and affects the structure of their kinase domains and autoinhibitory segments. But these effects are much stronger on CaMKK1 than on CaMKK2 because the CaMKK1:14-3-3γ complex has a more compact and rigid structure in which the active site of the kinase domain directly interacts with the last two C-terminal helices of the 14-3-3γ protein, thereby inhibiting CaMKK1. In contrast, the CaMKK2:14-3-3 complex has a looser and more flexible structure, so 14-3-3 binding only negligibly affects the catalytic activity of CaMKK2. Therefore, Ca2+/CaM binding suppression and the interaction of the kinase active site of CaMKK1 with the last two C-terminal helices of 14-3-3γ protein provide the structural basis for 14-3-3-mediated CaMKK1 inhibition.

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

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2023

Confidentiality

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

Name of the periodical

Protein Science

ISSN

0961-8368

e-ISSN

1469-896X

Volume of the periodical

32

Issue of the periodical within the volume

11

Country of publishing house

US - UNITED STATES

Number of pages

17

Pages from-to

e4805

UT code for WoS article

001086113900001

EID of the result in the Scopus database

2-s2.0-85174803480