H. sapiens Caspase-3

Alex Seaver '17 and Coire Gavin-Hanner '18


I. Introduction

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Cysteine Asp-specific Proteases (CASPASEs) are enzymes that play important roles in Apoptosis and inflammation. The Caspases identified thus far can be organized into three groups: Inflammation Caspases (1, 4, 5, 11, and 12), Initiator Caspases (2, 8, 9, 10), and Executioner Caspases (3, 6, and 7). Caspase-3 is a key executioner enzyme that, in addition to Caspase-7, is necessary for apoptosis and normal mammalian life.
In healthy cells, Caspases exist as inactive procaspase composed of a Large subunit (p20), a small subunit (p10), and a prodomain of varying length. Once activated, the prodomains form a heterodimer with two subunits. Two heterodimers form a heterotetramer in a mature Caspase. Caspases may play a role in many diseases such as Alzheimer's. Their implication in such diseases makes them very attractive targets for drugs.

II. Procaspase and Activation

In healthy cells Caspase-3 exists as Procaspase-3, a homodimer made up of 17 kDa and 12 kDa subunits. There are two pathways that activate Procaspase-3, the extrinsic and intrinsic. The extrinsic pathway is activated by a TNFR1-binding substrate, a signal from outside of the cell to begin apoptosis. This pathway activates Caspase-8, an initiator Caspase which can cleave the Procaspase-3 homodimer. The intrinsic pathway is activated from within the cell itself as a self-recognition of damage. The intrinsic pathway activates Caspase-9, an initiator Capsase similar to Caspase-8.

III. General Structure

The mature Caspase is a homodimer of heterodimers, each formed from the and subunits of the procaspase. At their core, each heterodimer has six surrounded by five . The heterodimers are held together mostly by hydrophobic interactions. Some electrostatic interactions are also present.

IV. Active Site

The active site is made up of four loops. Loops and 4 bind with the substrate and provide selectivity.

V. Binding and Catalytic Activity

VI. References

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