Characterization of the human endogenous retrovirus K proteinase

Schommer, S.; Sauter, Marlies; Kräusslich, Hans‐Georg; Best, Barbara; Mueller‐Lantzsch, Nikolaus

doi:10.1099/0022-1317-77-2-375

Cited by 35 publications

(41 citation statements)

References 10 publications

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“…Active site mutant of full-length HERV-K10 protease was not enzymatically active, as expected. These results seem to be consistent with differential cleavage of HIV-1 Gag and Pol precursors by HERV-K10 protease in the context of chimeric virions, where the HERV enzyme cleaved HIV-1 polyproteins at both apparently authentic as well as nonauthentic sites (17,38).…”

Section: Expression and Purification Of Herv-k10supporting

confidence: 71%

“…6). Schommer et al (17) showed that presence of high concentration of HIV-1 protease inhibitor Ro 31-8959 (saquinavir) can inhibit autoprocessing of HERV-K10 protease in E. coli expression broth, suggesting a similarity between active sites of the two viral proteases. We therefore decided to test a series of our cyclic ureas, second generation HIV protease inhibitors (reviewed in Ref.…”

Section: Discussionmentioning

confidence: 99%

“…The existence of a functional HERV-K protease was inferred from the presence of processed Gag proteins in teratocarcinoma cells (5). Direct evidence for a functional protease activity came from expression of different clones in E. coli (15,17,25,38).…”

Section: Discussionmentioning

confidence: 99%

“…Typically the coding regions of HERV-K elements are far less disrupted by mutations than other HERV families, and protein synthesis has been observed for all the main retroviral genes. The HERV-K Gag precursors are cleaved into major core, matrix, and nucleocapsid components (14 -16), presumably by HERV-K protease, because functional activity has been demonstrated for this enzyme (15,17).…”

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confidence: 99%

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Inhibition of Human Endogenous Retrovirus-K10 Protease in Cell-free and Cell-based Assays

Kuhelj¹,

Rizzo²,

Chang

et al. 2001

Journal of Biological Chemistry

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A full-length and C-terminally truncated version of human endogenous retrovirus (HERV)-K10 protease were expressed in Escherichia coli and purified to homogeneity. Both versions of the protease efficiently processed HERV-K10 Gag polyprotein substrate. HERV-K10 Gag was also cleaved by human immunodeficiency virus, type 1 (HIV-1) protease, although at different sites. To identify compounds that could inhibit protein processing dependent on the HERV-K10 protease, a series of cyclic ureas that had previously been shown to inhibit HIV-1 protease was tested. Several symmetric bisamides acted as very potent inhibitors of both the truncated and full-length form of HERV-K10 protease, in subnanomolar or nanomolar range, respectively. One of the cyclic ureas, SD146, can inhibit the processing of in vitro translated HERV-K10 Gag polyprotein substrate by HERV-K10 protease. In addition, in virus-like particles isolated from the teratocarcinoma cell line NCCIT, there is significant accumulation of Gag and Gag-Pol precursors upon treatment with SD146, suggesting the compound efficiently blocks HERV-K Gag processing in cells. This is the first report of an inhibitor able to block cell-associated processing of Gag polypeptides of an endogenous retrovirus.

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Section: Expression and Purification Of Herv-k10supporting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Inhibition of Human Endogenous Retrovirus-K10 Protease in Cell-free and Cell-based Assays

Kuhelj¹,

Rizzo²,

Chang

et al. 2001

Journal of Biological Chemistry

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“…The precursor is processed by the virusencoded protease and the mature proteins are released. Active recombinant protease and reverse transcriptase enzymes have been successfully expressed in vitro (29,30). Without the ribosomal frameshifts, only a Gag protein of 76 kDa is translated.…”

Section: Herv-k Protein Expressionmentioning

confidence: 99%

Retroelements and the human genome: New perspectives on an old relation

Bannert

Kurth

2004

Proc. Natl. Acad. Sci. U.S.A.

468

423

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Retroelements constitute a large portion of our genomes. One class of these elements, the human endogenous retroviruses (HERVs), is comprised of remnants of ancient exogenous retroviruses that have gained access to the germ line. After integration, most proviruses have been the subject of numerous amplifications and have suffered extensive deletions and mutations. Nevertheless, HERV-derived transcripts and proteins have been detected in healthy and diseased human tissues, and HERV-K, the youngest, most conserved family, is able to form virus-like particles. Although it is generally accepted that the integration of retroelements can cause significant harm by disrupting or disregulating essential genes, the role of HERV expression in the etiology of malignancies and autoimmune and neurologic diseases remains controversial. In recent years, striking evidence has accumulated indicating that some proviral sequences and HERV proteins might even serve the needs of the host and are therefore under positive selection. The remarkable progress in the analysis of host genomes has brought to light the significant impact of HERVs and other retroelements on genetic variation, genome evolution, and gene regulation.A lmost half of the mammalian genome is derived from ancient transposable elements. The two general types, (DNA)-transposons and retroelements, often regarded as ''selfish DNA parasites or junk DNA,'' encompass Ϸ2.8% and 42.2% of the human genome, respectively (1, 2). This striking finding is one of the many insights from recent large-scale sequencing projects that have provided the most valuable information in this field since the initial discovery of mobile elements in 1956 by Barbara McClintock (3, 4). Whereas DNA-transposons amplify without an RNA intermediate, retroelements rely on an RNA transcript that is retrotranscribed by a reverse transcriptase before integration in the genome. Here, we briefly review the characteristics of retroelements, their present classification, and the available evidence for their biological significance and function in normal and pathological processes. The focus is on human endogenous retroviruses (HERVs), the remnants of ancient germ-cell infections. Although most of the HERV proviruses have undergone extensive deletions and mutations, some have retained ORFs coding for functional proteins. A few families, including the HERV-K (HML-2) group, have been shown to form viral particles (5, 6), and an apparently intact provirus has recently been discovered in a small fraction of the human population, indicating a very recent acquisition (5-7). Classification of RetroelementsRetroelements constitute 90% of the Ϸ3 million transposable elements present in the human genome (1). They are split into two large groups, the non-LTR and LTR elements (Fig. 1). Two of the non-LTR members are present in extremely high copy numbers in the mammalian germ line: the short interspersed elements (SINE) with the prominent Alu and MIR repeats and the long-terminal interspersed elements (LINE) containing the...

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human endogenous retrovirus K endopeptidase 3.4.23.50

Schomburg¹,

Schomburg²

2013

Class 3.4–6 Hydrolases, Lyases, Isomerases, Ligases

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Characterization of the human endogenous retrovirus K proteinase

Cited by 35 publications

References 10 publications

Inhibition of Human Endogenous Retrovirus-K10 Protease in Cell-free and Cell-based Assays

Inhibition of Human Endogenous Retrovirus-K10 Protease in Cell-free and Cell-based Assays

Retroelements and the human genome: New perspectives on an old relation

human endogenous retrovirus K endopeptidase 3.4.23.50

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