14-3-3 proteins inactivate DAPK2 by promoting its dimerization
and protecting key regulatory phosphosites

J 2021

14-3-3 proteins inactivate DAPK2 by promoting its dimerization and protecting key regulatory phosphosites

HORVATH, M., O. PETRVALSKA, P. HERMAN, V. OBSILOVA, T. OBSIL et. al.

Základní údaje

Originální název

14-3-3 proteins inactivate DAPK2 by promoting its dimerization and protecting key regulatory phosphosites

Autoři

HORVATH, M., O. PETRVALSKA, P. HERMAN, V. OBSILOVA a T. OBSIL

Vydání

COMMUNICATIONS BIOLOGY, 2021, 2399-3642

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10600 1.6 Biological sciences

Stát vydavatele

Německo

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 6.548

Kód RIV

RIV/00216224:14740/21:00124530

Organizační jednotka

Středoevropský technologický institut

DOI

http://dx.doi.org/10.1038/s42003-021-02518-y

UT WoS

000686777300004

Klíčová slova anglicky

INTRINSICALLY DISORDERED PROTEINSSERINE/THREONINE KINASESTRUCTURAL BASISBINDINGINHIBITIONAPOPTOSISRAFDIFFERENTIATIONRECOGNITIONACTIVATION

Štítky

ne MU, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 18. 5. 2022 15:00, Mgr. Pavla Foltynová, Ph.D.

Anotace

V originále

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.

Návaznosti

90127, velká výzkumná infrastruktura

Název: CIISB II

Citovat

HORVATH, M., O. PETRVALSKA, P. HERMAN, V. OBSILOVA a T. OBSIL. 14-3-3 proteins inactivate DAPK2 by promoting its dimerization and protecting key regulatory phosphosites. COMMUNICATIONS BIOLOGY. 2021, roč. 4, č. 1, s. 986-999. ISSN 2399-3642. Dostupné z: https://dx.doi.org/10.1038/s42003-021-02518-y.

@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 a T. OBSIL. 14-3-3 proteins inactivate DAPK2 by promoting its dimerization and protecting key regulatory phosphosites. \textit{COMMUNICATIONS BIOLOGY}. 2021, roč.~4, č.~1, s.~986-999. ISSN~2399-3642. Dostupné z: https://dx.doi.org/10.1038/s42003-021-02518-y.

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