Modelling, synthesis and biological activity of a BLV proteinase, made of (only) 116 amino acids

Précigoux, G.; Geoffre, S.; Léonard, Renaud; Llido, S.; Dautant, Alain; d’Estaintot, Béatrice Langlois; Picard, Philippe; Ménard, Armelle; Guillemain, Bernard

doi:10.1016/0014-5793(93)81798-5

Cited by 13 publications

(4 citation statements)

References 14 publications

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“…The function of the Cterminal extension (aa 116-125) is controversial. Based on some previous studies, these residues were not required for activity of the HTLV-1 PR (Precigoux et al, 1993;Herger et al, 2004), whilst five of the C-terminal residues (aa 116-120) appeared to be important in another study (Hayakawa et al, 1992). The final model of the BLV PR dimer with substrate had a root mean square (rms) difference of 0.79 Å (0.079 nm) for 223 pairs of Ca atoms compared with the crystal structure of the HTLV-1 PR, and 1.72 Å for 175 pairs of Ca atoms compared with the crystal structure of the HIV-1 PR (with PDB code 2AOD).…”

Section: Resultsmentioning

confidence: 90%

Bovine leukemia virus protease: comparison with human T-lymphotropic virus and human immunodeficiency virus proteases

Sperka

Miklóssy

Tie

et al. 2007

Journal of General Virology

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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.

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Section: Resultsmentioning

confidence: 90%

Bovine leukemia virus protease: comparison with human T-lymphotropic virus and human immunodeficiency virus proteases

Sperka

Miklóssy

Tie

et al. 2007

Journal of General Virology

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“…On the other hand, the activity mutant was not purified and tested further. On the other hand, a BLV protease mutant in which the ten C-terminal of HIV-1 protease has been reported to be independent of sodium ion concentration, but decreases upon an residues were deleted has been reported and it retains proteolytic activity [24]. Recently, a mutant of HTLV-I increase in magnesium ion concentration [31].…”

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confidence: 99%

Understanding HTLV-I Protease

Shuker

Mariani

Herger

et al. 2003

Chemistry & Biology

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genome [11]. It is made up of the genes gag, pro, pol, and env flanked by long terminal repeats on each end, School of Chemistry and Biochemistry Georgia Institute of Technology and expression of the genome yields Gag and Gag-Pro-Pol polyprotein precursors [12, 13]. HTLV-I protease is Atlanta, Georgia 30332 encoded in a different reading frame than the Gag precursor and spans from the 3Ј end of the gag region to the 5Ј end of pol region. Synthesis of the protease occurs Human T cell leukemia virus type I (HTLV-I) is a human by ribosomal frameshifting [14], and a second ribosomal retrovirus that has been clinically associated with adult frameshift produces the 95 kDa Pol polyprotein. Upon T cell leukemia/lymphoma, and it has been designated viral maturation, the retroviral protease (PR) cleaves the as a dangerous emerging pathogen by the Centers for 55 kDa Gag precursor into the matrix (MA), capsid (CA), Disease Control. Like other retroviruses, proteolytic and nucleocapsid (NC) proteins. The Pol polyprotein is processing of specific sites in polyprotein precursors cleaved into reverse transcriptase/RNase H (RT-RH) and by a retroviral protease is an essential step in the viral integrase (IN). Because of its essential role in viral replilife cycle. HTLV-I protease is a 28 kDa homodimeric cation, HTLV-I protease is an attractive target for the aspartic acid protease that has only modest homology development of inhibitors to treat HTLV-I infection. Howto other retroviral proteases. The enzymology of HTLV-I ever, it has received little attention compared to its more protease has only recently begun to be investigated, famous cousin HIV protease, which has been studied and although it shares many characteristics of other extensively. This review details what is known about the retroviral proteases, it exhibits distinct substrate activity, specificity, and inhibition of HTLV-I protease. specificity and different susceptibility to aspartic acid protease inhibitors. This review describes what has been reported to date on the structural characteriza-Retroviral Aspartic Acid Proteases tion, specificity, and inhibition of HTLV-I protease. Cellular aspartic proteases, which are grouped in the A1 family of aspartic proteases, contain two aspartic

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“…However, the organization of the PR polypeptides differs: in HIV-1, p6 Pol is located at the N terminus of PR, whereas in Mason-Pfizer monkey virus the 5-kDa protein is conjugated to the C terminus of PR (11). Small peptides, whose function is not known and which were conjugated to PR, were also found in human T-cell leukemia virus and bovine leukemia virus (25).…”

Section: Notes Lane 1) Free P6mentioning

confidence: 99%

A p6Pol-protease fusion protein is present in mature particles of human immunodeficiency virus type 1

Almog

Roller

Arad

et al. 1996

J Virol

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Human immunodeficiency virus type 1 (HIV-1) protease (PR) and p6 Pol are translated as part of the Gag-Pol polyprotein after a ribosomal frameshift. PR is essential to virus replication and is responsible for cleaving Gag and Gag-Pol precursors, but the role of p6 Pol in HIV-1 infection is poorly understood. Here, we report that (i) PR is present in mature HIV-1 virions primarily as a p6 Pol-PR fusion protein; (ii) HIV-1 PR cleaves viral precursor proteins expressed in bacterial cells at the Phe-Leu bond (positions 1639 to 1642) located at the junction of the NC and p6 Pol proteins, releasing the p6 Pol-PR fusion protein; and (iii) purified p6 Pol-PR fusion protein undergoes autocleavage in vitro at at least three sites.

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Modelling, synthesis and biological activity of a BLV proteinase, made of (only) 116 amino acids

Cited by 13 publications

References 14 publications

Bovine leukemia virus protease: comparison with human T-lymphotropic virus and human immunodeficiency virus proteases

Bovine leukemia virus protease: comparison with human T-lymphotropic virus and human immunodeficiency virus proteases

Understanding HTLV-I Protease

A p6Pol-protease fusion protein is present in mature particles of human immunodeficiency virus type 1

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