6GKF

Structure of 14-3-3 gamma in complex with caspase-2 14-3-3 binding motif Ser139

Summary for 6GKF

• Entry DOI: 10.2210/pdb6gkf/pdb
• Descriptor: 14-3-3 protein gamma, Caspase-2 (3 entities in total)
• Functional Keywords: complex, phosphorylation, 14-3-3 protein, caspase-2, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 16
• Total formula weight: 224283.82

Authors

Alblova, M.,Obsil, T.,Obsilova, V. (deposition date: 2018-05-20, release date: 2018-10-17, Last modification date: 2024-11-06)

Primary citation

Smidova, A.,Alblova, M.,Kalabova, D.,Psenakova, K.,Rosulek, M.,Herman, P.,Obsil, T.,Obsilova, V.
14-3-3 protein masks the nuclear localization sequence of caspase-2.
FEBS J., 285:4196-4213, 2018

PubMed Abstract: Caspase-2 is an apical protease responsible for the proteolysis of cellular substrates directly involved in mediating apoptotic signaling cascades. Caspase-2 activation is inhibited by phosphorylation followed by binding to the scaffolding protein 14-3-3, which recognizes two phosphoserines located in the linker between the caspase recruitment domain and the p19 domains of the caspase-2 zymogen. However, the structural details of this interaction and the exact role of 14-3-3 in the regulation of caspase-2 activation remain unclear. Moreover, the caspase-2 region with both 14-3-3-binding motifs also contains the nuclear localization sequence (NLS), thus suggesting that 14-3-3 binding may regulate the subcellular localization of caspase-2. Here, we report a structural analysis of the 14-3-3ζ:caspase-2 complex using a combined approach based on small angle X-ray scattering, NMR, chemical cross-linking, and fluorescence spectroscopy. The structural model proposed in this study suggests that phosphorylated caspase-2 and 14-3-3ζ form a compact and rigid complex in which the p19 and the p12 domains of caspase-2 are positioned within the central channel of the 14-3-3 dimer and stabilized through interactions with the C-terminal helices of both 14-3-3ζ protomers. In this conformation, the surface of the p12 domain, which is involved in caspase-2 activation by dimerization, is sterically occluded by the 14-3-3 dimer, thereby likely preventing caspase-2 activation. In addition, 14-3-3 protein binding to caspase-2 masks its NLS. Therefore, our results suggest that 14-3-3 protein binding to caspase-2 may play a key role in regulating caspase-2 activation. DATABASE: The atomic coordinates and structure factors have been deposited in the Protein Data Bank, www.ww pdb.org (PDB ID codes 6GKF and 6GKG).

PubMed: 30281929
DOI: 10.1111/febs.14670

Experimental method

X-RAY DIFFRACTION (2.598 Å)