Molecular mechanism of apoptosis: prediction of three-dimensional structure of caspase-6 and its interactions by homology modeling.

Caspases, the intracellular cysteine proteinases, play a central role in the process of programmed cell death. Caspases induce apoptosis through a highly integrated and regulated biological, biochemical, and genetic mechanism. Although proper execution of apoptosis is fundamental for cell growth artificial caspase inhibition can be considered in certain degenerative diseases. This realization has attracted attention towards caspases as likely targets for pharmaceutical intervention. Here we analyze the structure of caspase-6 and also predict the possible glycosylation, phosphorylation, and myristoylation sites as very little is known about the functional role of these post translational modifications in the caspase family. These studies are expected to improve our understanding of associations of caspases with other molecules and the possible role played in apoptosis. The predicted tertiary structure of caspase-6 as well as the enzyme complexed with its inhibitor (tetra-peptide aldehyde Ac-IETD-CHO) shows similar binding feature as seen in other caspases. Cys/His catalytic dyad for caspase-6 and -8 show possible involvement of a third component, i.e., Pro29 and Arg258 in caspase-6 and caspase-8, respectively. Changes in the length and nature of loop between alpha5 and beta9, involved in defining the S4 subsite, result in modification of P4 (Ile) site. These interactions provide detail of inhibitor binding on structural level and also help in designing mutants for structure-function studies of these enzymes.