Caspase

Caspase 8 final

Cas2 pdb

Caspase 3 final

Cas4 pdb

Apop1

Caspases are a family of enzymes that play essential roles in apoptosis (programmed cell death), necrosis, and inflammation. Caspases are cysteine proteases that cleave their substrate proteins at specific amino acid sequences. These enzymes are critical for the maintenance of cellular homeostasis, the immune response, and the development of an organism.

Classification

Caspases can be classified into two main groups based on their roles in apoptosis and inflammation:

1. Initiator caspases (such as caspase-2, -8, -9, and -10) are responsible for the initial steps in the signaling pathways. They cleave and activate the effector caspases. 2. Effector caspases (such as caspase-3, -6, and -7) are responsible for the execution phase of apoptosis, cleaving various cellular substrates leading to the morphological and biochemical changes associated with cell death.

A third group, inflammatory caspases (such as caspase-1, -4, -5, and -11), are involved in the processing of cytokines in the inflammatory response.

Structure

Caspases are synthesized as inactive precursors, known as procaspases, which undergo proteolytic cleavage to become active. The active enzyme typically consists of a large and a small subunit, which form a heterotetramer (two large and two small subunits) in the active enzyme. The active site of caspases contains a cysteine residue that interacts with the substrate's peptide bond, cleaving it at specific aspartic acid residues.

Mechanism of Action

The activation of initiator caspases is tightly regulated and often involves adaptor proteins that facilitate the formation of a complex where procaspases are cleaved to become active. Once activated, initiator caspases cleave and activate effector caspases, amplifying the apoptotic signal. Effector caspases then cleave a variety of cellular substrates, leading to the dismantling of the cell.

Role in Apoptosis

Apoptosis is a critical process in development and disease, removing unwanted or damaged cells without eliciting an inflammatory response. Caspases are central to the execution of apoptosis, with different caspases being activated in response to various apoptotic signals, including those from within the cell (intrinsic pathway) and those from outside the cell (extrinsic pathway).

Role in Inflammation

Inflammatory caspases, such as caspase-1, play a key role in the immune response by processing pro-inflammatory cytokines like IL-1β and IL-18 into their active forms. These caspases are activated within a multiprotein complex known as the inflammasome.

Clinical Significance

Dysregulation of caspase activity is associated with a variety of diseases, including cancer, neurodegenerative diseases, and autoimmune diseases. In cancer, the evasion of apoptosis is a hallmark, and caspases are often found to be downregulated or inactivated. Conversely, excessive caspase activity can contribute to the pathology of neurodegenerative and autoimmune diseases.

Therapeutic Targets

Given their central role in apoptosis and inflammation, caspases have been targeted for therapeutic intervention. Inhibitors of caspases are being explored as treatments for diseases characterized by excessive cell death, such as stroke and neurodegenerative diseases, while activators of caspases are being investigated as potential anti-cancer therapies.