Caspase-6 and neurodegeneration

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One of the CBI Molecules being studied in the University of Massachusetts Amherst Chemistry-Biology Interface Program at UMass Amherst and on display at the Molecular Playground.

Caspase-6 with Z-VAD-FMK, an inhibitor of caspase-6 activity, 3qnw

PhD Chemistry Student

University of Massachusetts Amherst Protein Regulation/Structural Biology of Caspase

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Caspase-6 and Neurodegeneration

Cysteine aspartate proteases (caspases) play several key roles in cellular development, homeostasis, and a wide range of diseases. These proteases are normally expressed in cells as inactive precursor zymogens and get activated during processes such as cellular death pathway known as apoptosis [1]. Caspase-6 is particularly interesting since it has been implicated in neurodegenerative diseases including Alzheimer’s and Huntington’s Disease. Alzheimer’s Disease is the major cause of cognitive and cerebral deterioration in older adults. Caspase-6 has been shown to cut amyloid precursor protein (APP), at position 720 leading to the toxic fragment Jcasp, which is one of the fragments possibly responsible for causing the disease morphology [2]. Specific amino acid sequence (IVLD586G) is recognized by caspase-6 in mice with Huntington’s disease that give rise to the development of the behavioral and neuropathological features of the disease [3] [4]. Mutation of the caspase-6 site in mice model with Alzheimer’s and Huntington’s disease provides protection from the neural dysfunction, suggesting a causal relationship between caspase-6 cleavage and neurodegeneration.

Structure and Regulation

The structure of caspase-6 [5] [6] is similar in overall fold to the six other human caspases for which structures are available, all of which are dimeric when active. The structure of ligand-free caspase-6 differs significantly from all other caspases because two novel extended helices are observed flanking the caspase-6 active site. All caspases share a common active-site cysteine–histidine dyad [7] and derive their name, cysteine aspartate proteases, from the presence of the catalytic cysteine at the active site and from their exquisite specificity for cleaving substrate proteins after aspartate residues [8]. Caspases catalyze cleavage of amide bonds via nucleophilic attack of the cysteine thiolate (Cys163 in caspase-6) at the substrate amide carbonyl. During catalysis, the histidine (His121 in caspase-6) activates the catalytic cysteine and a water molecule. Mutation of either of these residues results in loss of catalytic activity [9]. Caspase-6 is expressed as inactive zymogen capable of dimerization. Caspase-6 has three reported cleavage sites that appear to be cleaved by autoproteolysis and or other caspases: D23 in the prodomain, D179 and D193 in the intersubunit linker [10]. The prodomain is released from the caspase dimer after cleavage leaving the active form of enzyme consists of two large and two small subunits. The large subunits contain the active site catalytic dyad residues, and the small subunits contain most of the dimer interface and the allosteric site.

The regulation of caspase-6 activity is not well studied. More research on possible ways to regulate caspase-6 activity will provide additional basic understanding of the mechanism of caspase-6 activation. In cells, caspase-6 can be activated by removal of the part of caspase-6, the prodomain, along with cleavage at specific amino acid residue (aspartate 193). In addition, an alternatively spliced form of caspase-6, the caspase beta (C6β) isoform has been shown to inhibit caspase-6 activity [11]. Morover, reported structures of caspase-6 and its inhibitors (Ac-VEID-CHO [PDB ID: 3OD5] & (Z-VAD-FMK [PDB ID: 3QNW]) shed the some basic dynamics of caspase-6 activation including loop rearrangement near the active site [12] [13].

See Also

Crystal structure of ligand free human caspase-6


Crystal structure of human ligand-free mature caspase-6


Crystal structure of Caspase-6 zymogen


Crystal structure of active caspase-6 bound with Ac-VEID-CHO


See list of all caspase-6 structures in Caspase


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