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@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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