Other formats:
BibTeX
LaTeX
RIS
@article{1846840,
author = {Horvath, M. and Petrvalska, O. and Herman, P. and Obsilova, V. and Obsil, T.},
article_number = {1},
doi = {http://dx.doi.org/10.1038/s42003-021-02518-y},
keywords = {INTRINSICALLY DISORDERED PROTEINSSERINE/THREONINE KINASESTRUCTURAL BASISBINDINGINHIBITIONAPOPTOSISRAFDIFFERENTIATIONRECOGNITIONACTIVATION},
language = {eng},
issn = {2399-3642},
journal = {COMMUNICATIONS BIOLOGY},
title = {14-3-3 proteins inactivate DAPK2 by promoting its dimerization and protecting key regulatory phosphosites},
url = {https://www.nature.com/articles/s42003-021-02518-y.pdf},
volume = {4},
year = {2021}
}
TY - JOUR
ID - 1846840
AU - Horvath, M. - Petrvalska, O. - Herman, P. - Obsilova, V. - Obsil, T.
PY - 2021
TI - 14-3-3 proteins inactivate DAPK2 by promoting its dimerization and protecting key regulatory phosphosites
JF - COMMUNICATIONS BIOLOGY
VL - 4
IS - 1
SP - 986
EP - 986
SN - 23993642
KW - INTRINSICALLY DISORDERED PROTEINSSERINE/THREONINE KINASESTRUCTURAL BASISBINDINGINHIBITIONAPOPTOSISRAFDIFFERENTIATIONRECOGNITIONACTIVATION
UR - https://www.nature.com/articles/s42003-021-02518-y.pdf
N2 - Death-associated protein kinase 2 (DAPK2) is a CaM-regulated Ser/Thr protein kinase, involved in apoptosis, autophagy, granulocyte differentiation and motility regulation, whose activity is controlled by autoinhibition, autophosphorylation, dimerization and interaction with scaffolding proteins 14-3-3. However, the structural basis of 14-3-3-mediated DAPK2 regulation remains unclear. Here, we structurally and biochemically characterize the full-length human DAPK2:14-3-3 complex by combining several biophysical techniques. The results from our X-ray crystallographic analysis revealed that Thr369 phosphorylation at the DAPK2 C terminus creates a high-affinity canonical mode III 14-3-3-binding motif, further enhanced by the diterpene glycoside Fusicoccin A. Moreover, concentration-dependent DAPK2 dimerization is disrupted by Ca2+/CaM binding and stabilized by 14-3-3 binding in solution, thereby protecting the DAPK2 inhibitory autophosphorylation site Ser318 against dephosphorylation and preventing Ca2+/CaM binding. Overall, our findings provide mechanistic insights into 14-3-3-mediated DAPK2 inhibition and highlight the potential of the DAPK2:14-3-3 complex as a target for anti-inflammatory therapies. Horvath et al. structurally and biochemically characterize the full-length human DAPK2-14-3-3 complex to investigate the effects of binding to DAPK2 on its dimerization, activation by dephosphorylation of Ser318, and Ca2+/calmodulin binding. Their results provide mechanistic insights into 14- 3-3-mediated DAPK2 inhibition and highlight the potential of the DAPK2:14-3-3 complex as a target for anti-inflammatory therapies.
ER -
HORVATH, M., O. PETRVALSKA, P. HERMAN, V. OBSILOVA and T. OBSIL. 14-3-3 proteins inactivate DAPK2 by promoting its dimerization and protecting key regulatory phosphosites. \textit{COMMUNICATIONS BIOLOGY}. 2021, vol.~4, No~1, p.~986-999. ISSN~2399-3642. Available from: https://dx.doi.org/10.1038/s42003-021-02518-y.
|
