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Biological Function

Caspase-6 is a member of the Cysteine-Aspartic protease family, and involved in apoptosis. It is most notably involved in neurodegenerative diseases, such as Alzheimer's disease and dementia.

Caspase-6 involvement in Alzheimer's Disease

Caspase-6 activity is associated with the formation of lesions within the Alzheimer's Disease (AD) and they can become present very early on during the disease's progression. Proapoptotic protein p53 is present at increased levels within AD brains, which seems to directly increase the transcription of Caspase-6. Treatments of Alzheimer's include targeting active Caspase-6 proteins because staining has found active Caspase-6 within the hippocampus and cortex of the Brain within in mild, moderate, and severe cases of AD, which indicates that Caspase-6 plays a predominate role in the pathophysiology of Alzheimer's. There has been research conducted that shows activation of Caspase-6 in AD could cause disruption of the cytoskeleton network of neurons, which then causes handicapped synaptic plasticity.

Structural Overview

Inactive State

Active State

Originally it was thought to be cleaved and activated by a combination of Caspases-3 and -7, but research has shown that Caspase-6 enters the active state by self-cleaving at residue 193 after a sequence of TEVD. The protein then becomes a Tetramer of Dimers.

Figure Legend

Mechanism of Action

Caspase-6 has a small pro-domain. It shares 41% sequence identity with Caspase-3 and 37% sequence identity with Caspase-7. Both of these caspases are classified as effectors and because of it's similarites to these other Caspases, Caspase-6 is also classified as an effector. Caspase-6, does however, have many unique features compared to the other effectors, it has similar substrate specificity to that of initiator Caspases-8 and -9. Inhibitors of Apoptosis or IAPs, which are known to inhibit Caspase-3, -7, and -9, do not inhibit Caspase-6. Caspase-6 is known to undergo self-processing and activation in vitro and in vivo. High activity of Caspase-6 protein do not induce apoptosis of in HEK293 cells. Caspase-6 also has a relatively low zymogenicty, which is the ratio of activity for cleaved protein to the activity of uncleaved protein, of about 200, which is comparable to the zymogenicities of Caspase-8 and Caspase-9, which are both classified as initiator caspases. Caspase-6’s zymogenicity is also much lower than Caspase-3, which is another effector. This is interesting because the Caspase-6 protein shows low activity when it is not cleaved, similar to the initiator caspases, but Caspase-3, another effector, has basically no zymogen activity. Caspase-6 is classified as an effector, but it can also act as an initiator and cleave Caspases-2 and -8. It can also induce the mitochondrial membrane to become permeable, which leads to cytochrome c release and activation of other effector caspases.

Activation of Caspase-6

It is expressed as a dimeric zymogen, it contains a short prodomain, a large subunuit, known as p20, an intersubunit linker, and a small subunit, known as p10. Caspase-6 contains three cleavage sites, the first following the residues TETD23 that follows the prodomain, the next sit follows the residue sequence DVVD179, and the third cleavage site falls within the intersubunit linker following the sequence TEVD193. To activate effector caspases there must be a cleavage at the intersubunit linker, which releases the N terminus of p10, the N terminus then rotates about 180⁰ to form a loop bundle with the four other loops of an adjacent catalytic unit, this stabilizes the substrate binding pockets. It is sufficient to cleave either or both of the intersubunit linkers to activate Caspase-6. It is also important to point out that the prodomain of Caspase-6 inhibits in vivo. Caspase-6 can either undergo autoactivation or it can be activated by Capase-3, but the patterns for these two modes of activation are different. When Caspase-6 is self-activating it loses the prodomain first by cleavage at TETD23. Then it self-cleaves at TEVD23, which results in the formation of the loop bundle. The final cleavage of autoactivation is at DVVD179. In comparison, when Caspase-3 is activating Caspase-6 the first cleavage is at DVVD179, then the next cleavage is at TETD23, and the final cleavage occurs at TEVD193.

Autoactivation Mechanism of Caspase-6

It has been found that Caspase-6 can undergo activation without any other caspases, in vivo and in vitro, so there is a proposed intramolecular self-cleavage mechanism for Caspase-6. The intramolecular cleavage of TEVD193 is essential for the initiation caspase-6 activation without Caspase-3 present. The prodomain somehow inhibits the intramolecular cleavage of TEVD193, but currently the mechanism for this is unknown. The TETD23 and TEVD193 cleavage sites are similar, but the TETD23 cleavage site is always cleaved before TEVD193. This indicates that the TETD23 cleavage site is always more readily available for cleavage. The result of the TETD23 cleavage site priority is that the prodomain acts as a “suicide protector”, which protects the TEVD193 cleavage site from intermolecular self-cleavage. This protection is useful when there are low levels of protein, such as when it is in vivo, it also helps explain why the prodomain inhibits self-activation in vivo, but not in vitro.

Zinc Ligand(s)

The Zinc ligand is known to inhibit the Caspase-6 protein.

Other Ligands

Other ligands that bind to Caspase-6 are caspase-8, which is activated within the caspase-chain by Caspase 6. After it being activated by Caspase-6, Caspase-8 is then in it's active state. Caspase-6 has been know to be a self-activator, so other Caspase-6 proteins are also known to be ligands that are bound at the active site.