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Introduction

The word “Caspase” stands for “Cysteine dependant aspartate directed protease” and represents a whole family of proteins (12). Proteins of the caspase family are essential enzymes involved in inflammation, necrosis and apoptosis process.

General fonction and mechanism

During the programmed cell death process, an apoptotic signal activates initiator caspases which gather in large protein complexes where they autoactivate. Then, they are able to activate in turn other capsases, called executioner caspases. Once activated, these executioner caspases will activate effectors which will finally lead to the cell apoptosis. Caspase 7 is one of these executioner caspase.

Structure of the Caspase-7

The structure of the caspase-7 results directly from the maturation of the procaspase-7 zymogen by an initiator caspase. (cf. wiki)

1) Structure of the Procaspase-7

In the cytoplasm, caspases are not already, constitutively present in their active form. They exist as free cytoplasmic inactive precursors called procaspases.

Procaspase-7 is a homodimeric globular-303 amino-acids long polypeptide. This protein contains , representing two catalytic units. Each of these monomers is composed by a central 6-stranded β-sheet and 5 α-helices, forming a and a subunit, linked by a . The homodimerization is performed thanks to hydrophobic interactions between the 6 β-strands of each monomer. This homodimer is organized in a “open α/β barrel fold”.

Four loops (L1 to L4), located at the two opposite ends of the β–sheet, emanate from each homodimer and define the shape of the catalytic groove of each monomer.

links the two the large and small subunit of each procaspase-7 monomer. In the procaspase-7, this loop is in a “closed” conformation that precludes any possibility of substrate or inhibitor binding to the yet incomplete active site. Thus, in this considered conformation, the enzyme is yet inactive. This highly flexible loop contains two cleavage sites (Asp198 - Asp207) which are essential to the maturation of the Procaspase-7 (cf MATURATION). It also contains an essential residue needed for the catalytic activity of the Caspase-7 :

is a part of the large subunit, while and belong to the small subunit of each monomer. These three loops will also participate in the formation of the catalytic site.

The 23 last amino acids of the N-ter extremity of procaspase-7 define a “prodomain”. This prodomain is apparently implicated in an inhibitory mechanism that maintains the procaspase (or caspase) catalytically inactive until it is cleaved. The mechanism by which the prodomain could inhibit caspase-7 enzymatic activity is still unclear.

Comparison with the Caspase-3

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