Caspase-6 is an endopeptidase involved in apoptosis. In terms of its catalytic function, it is a part of the cysteine-aspartate family. Before Caspase-6 becomes functional, the enzyme exists as a , also known as a zymogen. This zymogen exists as a , whose are then cleaved at to assume its active conformation. Zymogen activation through cleavage is largely conserved across the caspase family. However, Caspase-6 is unique in that it becomes active through self-cleavage in addition to cleavage by a separate enzymes[1] The shift misaligns and disrupts residues found in the active site. This conformational difference prevents the intersubunit linker from entering during zymogen activation and the self-cleaved active dimer cannot be formed. Additionally, no new substrate is able to enter the active site.
Medical Relevance
Caspase-6 involvement in Alzheimer's Disease
Caspase-6 is known to be involved in many neurodegenerative diseases, one of which is Alzheimer's disease (AD). Caspase-6 activity is associated with the formation of lesions within the Alzheimer's Disease.Lesions can be found in early stages of AD[2]. A proapoptotic protein, p53, is present at increased levels within AD brains, which seems to directly increase the transcription of Caspase-6, which indirectly influences apoptosis of neurons. Future treatments of AD include selective inhibition of active Caspase-6 proteins; staining has found active Caspase-6 within the hippocampus and cortex of the brain within a varying severity of AD cases. This suggests that Caspase-6 plays a predominate role in the pathophysiology of AD. There has been research conducted that shows activation of Caspase-6 in AD could cause disruption of the cytoskeleton network of neurons and lead to neuronal apoptosis[2].
