Found at high concentrations in the brain and bordering tissues, Caspase-6 has been implicated in several neurological diseases including Alzheimer's and dementia. It's primarily involved in apoptosis through a largely ambiguous mechanism. It is classified as an [1]endopeptidase as it cleaves an internal peptide bond of its substrate. It has relatively low specificity in the binding site which allows for a variety of substrates, including other caspase enzymes to bind. Furthermore, it is a part of the cysteine aspartate family, which have these critical amino acid residues in the active site of the enzyme. Caspase-6 has both an inactive zinc-bound conformation and an active ligand-bound conformation, which are largely regulated by variations in zinc concentration.
Function
Structure
- Active Site
- Zinc Exosite
Inhibition
- Zinc Inhibition
Primary inhibition of Caspase-6 occurs when a zinc ion binds to the exosite containing Lys-36, Glu-244, and His-287 of the active dimer. In addition to these residues, the zinc interacts with one water molecule from the cytoplasm. It has been proposed that helices of the active dimer must rotate or move in some other way to provide these ideal interactions with zinc. This subtle shift is most likely the cause for allosteric inhibition. As the helices move to bind zinc, the amino acids of the active site become misaligned. The altered positions of the amino acids no longer provide ideal interactions for incoming substrates. After zinc binds, no new substrates enter the active site. Thus, Caspase-6 is effectively inhibited.
- Phosphorylation
- Zymogen Activation
Relevance
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