The mechanism of activation of the adenovirus type 2 protease
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The adenovirus codes for a protease which is essential for virion infectivity. This protease requires the presence of a peptide cofactor in order to develop optimal activity. This peptide, GVQSLBCRRRCF, originates from the C-terminal of a viral protein, pVI, and some evidence regarding its specificity came from observations showing that neither of the peptides GVQSLKRRRAF or KRRRCF was able to activate the protease, indicating that both the cysteine and the N-terminal were important in the activation process. However, the mechanism by which the peptide activates the protease has never been elucidated. In this project, several factors contributing to the activation mechanism of the human adenovirus type 2 protease were studied, such as the peptide N-terminal length and composition, the environment close to the cysteine and the distance between the N-terminal and the cysteine, in view of assessing the relevance of each of these parameters in the activation process and proposing a mechanism of activation. Based on the above studies, attempts of protease inhibition were also performed based on the activation process rather than on the blocking of the active site, and the relevance of these results was related with the proposed activation mechanism. An attempt to clone an avian adenovirus protease was also performed, in order to try and compare the activation processes between the two proteases.
Thesis, PhD Doctor of Philosophy
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