Bovine leukemia virus protease: comparison with human T-lymphotropic virus and human immunodeficiency virus proteases.
Bovine leukemia virus (BLV) is a valuable model system for understanding human T-lymphotropic virus 1 (HTLV-1); the availability of an infectious BLV clone, together with animal-model systems, will help to explore anti-HTLV-1 strategies. Nevertheless, the specificity and inhibitor sensitivity of the BLV protease (PR) have not been characterized in detail. To facilitate such studies, a molecular model for the enzyme was built. The specificity of the BLV PR was studied with a set of oligopeptides representing naturally occurring cleavage sites in various retroviruses. Unlike HTLV-1 PR, but similar to the human immunodeficiency virus 1 (HIV-1) enzyme, BLV PR was able to hydrolyse the majority of the peptides, mostly at the same position as did their respective host PRs, indicating a broad specificity. When amino acid residues of the BLV PR substrate-binding sites were replaced by equivalent ones of the HIV-1 PR, many substitutions resulted in inactive protein, indicating a great sensitivity to mutations, as observed previously for the HTLV-1 PR. The specificity of the enzyme was studied further by using a series of peptides containing amino acid substitutions in a sequence representing a naturally occurring HTLV-1 PR cleavage site. Also, inhibitors of HIV-1 PR, HTLV-1 PR and other retroviral proteases were tested on the BLV PR. Interestingly, the BLV PR was more susceptible than the HTLV-1 PR to the inhibitors tested. Therefore, despite the specificity differences, in terms of mutation intolerance and inhibitor susceptibility of the PR, BLV and the corresponding animal-model systems may provide good models for testing of PR inhibitors that target HTLV-1.
Sperka
Tamás
T
Department of Biochemistry and Molecular Biology, Research Center for Molecular Medicine, Medical and Health Science Center, University of Debrecen, Hungary.
Miklóssy
Gabriella
G
Department of Biochemistry and Molecular Biology, Research Center for Molecular Medicine, Medical and Health Science Center, University of Debrecen, Hungary.
Tie
Yunfeng
Y
Department of Chemistry, Georgia State University, Atlanta, GA, USA.
Bagossi
Péter
P
Department of Biochemistry and Molecular Biology, Research Center for Molecular Medicine, Medical and Health Science Center, University of Debrecen, Hungary.
Zahuczky
Gábor
G
Department of Biochemistry and Molecular Biology, Research Center for Molecular Medicine, Medical and Health Science Center, University of Debrecen, Hungary.
Boross
Péter
P
Department of Biology, Georgia State University, Atlanta, GA, USA.|Department of Biochemistry and Molecular Biology, Research Center for Molecular Medicine, Medical and Health Science Center, University of Debrecen, Hungary.
Matúz
Krisztina
K
Department of Biochemistry and Molecular Biology, Research Center for Molecular Medicine, Medical and Health Science Center, University of Debrecen, Hungary.
Harrison
Robert W
RW
Department of Computer Science, Georgia State University, Atlanta, GA, USA.|Department of Biology, Georgia State University, Atlanta, GA, USA.
Weber
Irene T
IT
Department of Biology, Georgia State University, Atlanta, GA, USA.|Department of Chemistry, Georgia State University, Atlanta, GA, USA.
Tözsér
József
J
Department of Biochemistry and Molecular Biology, Research Center for Molecular Medicine, Medical and Health Science Center, University of Debrecen, Hungary.
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002417:Cattle; D015497:HIV-1 / Q000201:enzymology* / Q000235:genetics*; D015368:Human T-lymphotropic virus 1 / Q000201:enzymology* / Q000235:genetics*; D006801:Humans; D066298:In Vitro Techniques; D001909:Leukemia Virus, Bovine / Q000201:enzymology* / Q000235:genetics*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D010447:Peptide Hydrolases / Q000235:genetics*; D011480:Protease Inhibitors / Q000494:pharmacology; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity; D013379:Substrate Specificity; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism
D010446:Peptide Fragments; D011480:Protease Inhibitors; D014764:Viral Proteins; D010447:Peptide Hydrolases