Characterization of the Protease of a Fish Retrovirus, Walleye Dermal Sarcoma Virus

Fodor, Sharon K.; Vogt, Volker M.

doi:10.1128/jvi.76.9.4341-4349.2002

Cited by 13 publications

(11 citation statements)

References 35 publications

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“…This is again in good agreement with the optimal pH of other retropepsin-like [37], [38] enzymes as well as of the pepsin-like renin [53], [54] and, actually, it is consistent with the presence in APRc of an alanine residue downstream from the catalytic motif (Asp-Thr-Gly-Ala), instead of the common threonine residue found in most pepsin-like APs [27]. Together with the observed inhibitory effect of specific HIV-1 PR inhibitors, these results strengthen the striking resemblance between the enzymatic properties of APRc and those of viral retropepsins.…”

Section: Discussionsupporting

confidence: 86%

RC1339/APRc from Rickettsia conorii Is a Novel Aspartic Protease with Properties of Retropepsin-Like Enzymes

et al. 2014

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Members of the species Rickettsia are obligate intracellular, gram-negative, arthropod-borne pathogens of humans and other mammals. The life-threatening character of diseases caused by many Rickettsia species and the lack of reliable protective vaccine against rickettsioses strengthens the importance of identifying new protein factors for the potential development of innovative therapeutic tools. Herein, we report the identification and characterization of a novel membrane-embedded retropepsin-like homologue, highly conserved in 55 Rickettsia genomes. Using R. conorii gene homologue RC1339 as our working model, we demonstrate that, despite the low overall sequence similarity to retropepsins, the gene product of rc1339 APRc (for Aspartic Protease from Rickettsia conorii) is an active enzyme with features highly reminiscent of this family of aspartic proteases, such as autolytic activity impaired by mutation of the catalytic aspartate, accumulation in the dimeric form, optimal activity at pH 6, and inhibition by specific HIV-1 protease inhibitors. Moreover, specificity preferences determined by a high-throughput profiling approach confirmed common preferences between this novel rickettsial enzyme and other aspartic proteases, both retropepsins and pepsin-like. This is the first report on a retropepsin-like protease in gram-negative intracellular bacteria such as Rickettsia, contributing to the analysis of the evolutionary relationships between the two types of aspartic proteases. Additionally, we have also shown that APRc is transcribed and translated in R. conorii and R. rickettsii and is integrated into the outer membrane of both species. Finally, we demonstrated that APRc is sufficient to catalyze the in vitro processing of two conserved high molecular weight autotransporter adhesin/invasion proteins, Sca5/OmpB and Sca0/OmpA, thereby suggesting the participation of this enzyme in a relevant proteolytic pathway in rickettsial life-cycle. As a novel bona fide member of the retropepsin family of aspartic proteases, APRc emerges as an intriguing target for therapeutic intervention against fatal rickettsioses.

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Section: Discussionsupporting

confidence: 86%

RC1339/APRc from Rickettsia conorii Is a Novel Aspartic Protease with Properties of Retropepsin-Like Enzymes

et al. 2014

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“…WDSV is associated with skin tumors in walleyes and it is the prototype of the epsilonretrovirus genus [76]. WDSV cleavage sites were inferred from the N-terminal sequence data on purified viral proteins [77].…”

Section: Epsilon Retroviral Proteasesmentioning

confidence: 99%

Comparative Studies on Retroviral Proteases: Substrate Specificity

Tőzsér

2010

Viruses

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Exogenous retroviruses are subclassified into seven genera and include viruses that cause diseases in humans. The viral Gag and Gag-Pro-Pol polyproteins are processed by the retroviral protease in the last stage of replication and inhibitors of the HIV-1 protease are widely used in AIDS therapy. Resistant mutations occur in response to the drug therapy introducing residues that are frequently found in the equivalent position of other retroviral proteases. Therefore, besides helping to understand the general and specific features of these enzymes, comparative studies of retroviral proteases may help to understand the mutational capacity of the HIV-1 protease.

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“…MMLV protease was cloned with maltose binding protein (MBP) and hexahistidine tags and purified as described previously (7). HTLV-1 protease (15), BLV protease (49), and WDSV protease (11) were purified from inclusion bodies after expression as described previously. HFV protease was cloned in fusion with MBP and used in its fusion form (10).…”

Section: Retroviral Proteasesmentioning

confidence: 99%

Amino Acid Preferences for a Critical Substrate Binding Subsite of Retroviral Proteases in Type 1 Cleavage Sites

Bagossi

Sperka

Fehér

et al. 2005

J Virol

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The specificities of the proteases of 11 retroviruses representing each of the seven genera of the family Retroviridae were studied using a series of oligopeptides with amino acid substitutions in the P2 position of a naturally occurring type 1 cleavage site (Val-Ser-Gln-Asn-Tyr2Pro-Ile-Val-Gln; the arrow indicates the site of cleavage) in human immunodeficiency virus type 1 (HIV-1). This position was previously found to be one of the most critical in determining the substrate specificity differences of retroviral proteases. Specificities at this position were compared for HIV-1, HIV-2, equine infectious anemia virus, avian myeloblastosis virus, MasonPfizer monkey virus, mouse mammary tumor virus, Moloney murine leukemia virus, human T-cell leukemia virus type 1, bovine leukemia virus, human foamy virus, and walleye dermal sarcoma virus proteases. Three types of P2 preferences were observed: a subgroup of proteases preferred small hydrophobic side chains (Ala and Cys), and another subgroup preferred large hydrophobic residues (Ile and Leu), while the protease of HIV-1 preferred an Asn residue. The specificity distinctions among the proteases correlated well with the phylogenetic tree of retroviruses prepared solely based on the protease sequences. Molecular models for all of the proteases studied were built, and they were used to interpret the results. While size complementarities appear to be the main specificity-determining features of the S2 subsite of retroviral proteases, electrostatic contributions may play a role only in the case of HIV proteases. In most cases the P2 residues of naturally occurring type 1 cleavage site sequences of the studied proteases agreed well with the observed P2 preferences.

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Characterization of the Protease of a Fish Retrovirus, Walleye Dermal Sarcoma Virus

Cited by 13 publications

References 35 publications

RC1339/APRc from Rickettsia conorii Is a Novel Aspartic Protease with Properties of Retropepsin-Like Enzymes

RC1339/APRc from Rickettsia conorii Is a Novel Aspartic Protease with Properties of Retropepsin-Like Enzymes

Comparative Studies on Retroviral Proteases: Substrate Specificity

Amino Acid Preferences for a Critical Substrate Binding Subsite of Retroviral Proteases in Type 1 Cleavage Sites

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