3S8E

Phosphorylation regulates assembly of the caspase-6 substrate-binding groove

Summary for 3S8E

• Entry DOI: 10.2210/pdb3s8e/pdb
• Related: 2WDP 3K7E 3NKF 3NR2 3OD5
• Descriptor: Caspase-6 (2 entities in total)
• Functional Keywords: phosphomimetic, caspase, apoptosis, zymogen, hydrolase, huntington's, alzheimer's, cancer, protease, cytosol
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P55212
• Total number of polymer chains: 8
• Total formula weight: 255772.56

Authors

Velazquez-Delgado, E.M.,Hardy, J.A. (deposition date: 2011-05-27, release date: 2012-04-11, Last modification date: 2023-11-01)

Primary citation

Velazquez-Delgado, E.M.,Hardy, J.A.
Phosphorylation regulates assembly of the caspase-6 substrate-binding groove.
Structure, 20:742-751, 2012

PubMed Abstract: Caspases, a family of apoptotic proteases, are increasingly recognized as being extensively phosphorylated, usually leading to inactivation. To date, no structural mechanism for phosphorylation-based caspase inactivation is available, although this information may be key to achieving caspase-specific inhibition. Caspase-6 has recently been implicated in neurodegenerative conditions including Huntington's and Alzheimer's diseases. A full understanding of caspase-6 regulation is crucial to caspase-6-specific inhibition. Caspase-6 is phosphorylated by ARK5 kinase at serine 257 leading to suppression of cell death via caspase-6 inhibition. Our structure of the fully inactive phosphomimetic S257D reveals that phosphorylation results in a steric clash with P201 in the L2' loop. Removal of the proline side chain alleviates the clash resulting in nearly wild-type activity levels. This phosphomimetic-mediated steric clash causes misalignment of the substrate-binding groove, preventing substrate binding. Substrate-binding loop misalignment appears to be a widely used regulatory strategy among caspases and may present a new paradigm for caspase-specific control.

PubMed: 22483120
DOI: 10.1016/j.str.2012.02.003

Experimental method

X-RAY DIFFRACTION (2.88 Å)