Počet záznamů: 1
14-3-3 proteins inactivate DAPK2 by promoting its dimerization and protecting key regulatory phosphosites
- 1.0545402 - FGÚ 2022 RIV GB eng J - Článek v odborném periodiku
Horváth, Matej - Petrvalská, Olivia - Herman, P. - Obšilová, Veronika - Obšil, Tomáš
14-3-3 proteins inactivate DAPK2 by promoting its dimerization and protecting key regulatory phosphosites.
Communications Biology. Roč. 4, č. 1 (2021), č. článku 986. E-ISSN 2399-3642
Grant CEP: GA ČR(CZ) GA19-00121S
Výzkumná infrastruktura: CIISB II - 90127
Institucionální podpora: RVO:67985823
Klíčová slova: protein structure and function * protein kinase * DAPK * 14-3-3 protein * apoptosis * phosphorylation
Obor OECD: Biochemistry and molecular biology
Impakt faktor: 6.268, rok: 2020
Způsob publikování: Open access
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.
Trvalý link: http://hdl.handle.net/11104/0322100
Počet záznamů: 1