The Effect of Mutant Peptide Cofactors on Adenovirus Protease Activity and Virus Infection
| Autor: | Joseph M. Weber, Angelique Ruzindana-Umunyana, Sucheta Sircar |
|---|---|
| Rok vydání: | 2000 |
| Předmět: |
Adenain
Protein Conformation medicine.medical_treatment Molecular Sequence Data Mutant Coenzymes Peptide Biology Fluorescence Cell Line Conserved sequence Virology Enzyme Stability medicine Humans Amino Acid Sequence Disulfides Conserved Sequence chemistry.chemical_classification Cofactor binding Binding Sites Protease Dose-Response Relationship Drug Adenoviruses Human Virus Assembly Cysteine protease In vitro Enzyme Activation Molecular Weight Cysteine Endopeptidases chemistry Biochemistry Mutation Peptides Sequence Alignment Protein Binding |
| Zdroj: | Virology. 270:173-179 |
| ISSN: | 0042-6822 |
| Popis: | Adenoviruses encode a cysteine protease, adenain, required for uncoating and virion maturation. Adenain activity is regulated by an 11-amino-acid peptide cofactor thiol-bonded distal to the active site. Structural and experimental data suggest that the peptide might stabilize adenain in an optimal conformation for enzyme activity by bridging two noncontiguous regions of the molecule. The sequence requirements for this mechanism were examined both in vitro and ex vivo by means of mutant peptides and databank analysis. The results of in vitro experiments suggested that activation is not an all or nothing mechanism. With the exception of the smallest peptide, the mutant peptides bound to adenain, activated it, and competed with the wild-type peptide, but all of this occurred with reduced efficiency. When added to the medium of infected cells, most of the peptides inhibited infectious virus production to varying degrees in a dose-dependent manner and in accordance with their in vitro activity on adenain. We interpret this inhibition to be due to unscheduled adenain activation. Examination of the activation peptide sequences from 19 adenovirus serotypes revealed a limited number of conserved sequence features. These features were in agreement with the experimental data. We conclude that binding and activation of adenain by pVIc may be reversible and this reversibility may be an integral aspect of the in vivo regulation of enzyme activity in the course of virus assembly. The peptide cofactor binding domain is therefore a potential target for the development of anti-adenoviral agents. |
| Databáze: | OpenAIRE |
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