A new apo-caspase-6 crystal form reveals the active conformation of the apoenzyme

Area of Science:

• Biochemistry
• Structural Biology
• Neuroscience

Background:

• Caspase-6 is implicated in neurodegenerative diseases like Alzheimer's and Huntington's.
• Previous structural studies presented conflicting conformations of apo-caspase-6.
• The canonical conformation was observed in zymogen and inhibitor-bound forms, but not in the mature apoenzyme.

Purpose of the Study:

• To resolve the conformational ambiguity of mature apo-caspase-6.
• To present a new crystal structure of apo-caspase-6 in its canonical conformation.
• To compare this structure with the inhibitor-bound form to understand ligand-induced conformational changes.

Main Methods:

• X-ray crystallography to determine the structure of apo-caspase-6.
• Comparison of the new apoenzyme structure with the previously determined Ac-VEID-CHO caspase-6 inhibitor complex structure.

Main Results:

• A new crystal form of apo-caspase-6 in the canonical conformation was identified.
• The previous apo-caspase-6 structure was identified as a pH-inactivated form.
• Structural comparison revealed the organization of loops L2, L3, and L4 upon inhibitor binding and catalytic groove formation.

Conclusions:

• Mature apo-caspase-6 adopts a canonical conformation, resolving previous discrepancies.
• Understanding these conformational changes is crucial for designing effective caspase-6 inhibitors.
• This structural insight advances drug development strategies for neurodegenerative diseases involving caspase-6.