Functional Characterization of the Protease of Human Endogenous Retrovirus, K10: Can It Complement HIV-1 Protease?

To investigate the biochemical properties of the protease encoded by the human endogenous retrovirus, K10 (HERV-K), 213 amino acids of the 3‘-end of the HERV-K protease (PR) open reading frame were expressed in Escherichia coli. Autocatalytic cleavage of the expressed polypeptide resulted in an 18.2...

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Published in:	Biochemistry (Easton) Vol. 37; no. 49; pp. 17137 - 17144
Main Authors:	Towler, Eric M, Gulnik, Sergei V, Bhat, T. N, Xie, Dong, Gustschina, Elena, Sumpter, Terry R, Robertson, Nicole, Jones, Christopher, Sauter, Marlies, Mueller-Lantzsch, Nikolaus, Debouck, Christine, Erickson, John W
Format:	Journal Article
Language:	English
Published:	United States American Chemical Society 08-12-1998
Subjects:	AIDS/HIV Amino Acid Sequence Aspartic Acid Endopeptidases - chemistry Aspartic Acid Endopeptidases - metabolism Binding Sites Capsid - metabolism Catalysis Dimerization Endogenous Retroviruses - enzymology Enzyme Stability Escherichia coli gag Gene Products, Human Immunodeficiency Virus Gene Products, gag - metabolism HIV Antigens - metabolism HIV Protease - chemistry HIV Protease - metabolism human endogenous retrovirus Humans Hydrogen-Ion Concentration Models, Molecular Molecular Sequence Data Molecular Weight Protein Processing, Post-Translational Retrovirus Structure-Activity Relationship Viral Proteins
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Summary:	To investigate the biochemical properties of the protease encoded by the human endogenous retrovirus, K10 (HERV-K), 213 amino acids of the 3‘-end of the HERV-K protease (PR) open reading frame were expressed in Escherichia coli. Autocatalytic cleavage of the expressed polypeptide resulted in an 18.2 kDa protein which was shown to be proteolytically active against a fluorogenic peptide used as a substrate for HIV-1 protease. On the basis of sequence homology and molecular modeling, the 106 N-terminal amino acids of HERV-K PR were predicted to comprise a retroviral protease core domain. An 11.6 kDa protein corresponding to this region was expressed and shown to be a fully functional enzyme. The 11.6 kDa domain of HERV-K PR is unusually stable over a wide pH range, exhibits optimal catalytic activity between pH 4.0 and 5.0, and exists as a dimer at pH 7.0 with a K d of 50 μM. Like HIV-1 PR, the HERV-K PR core domain is activated by high salt concentrations and processes HIV-1 matrix-capsid polyprotein at the authentic HIV-1 PR recognition site. However, both the 18.2 and 11.6 kDa forms of HERV-K PR were highly resistant to a number of clinically useful HIV-1 PR inhibitors, including ritonavir, indinavir, and saquinavir. This raises the possibility that HERV-K PR may complement HIV-1 PR during infection, and could have implications for protease inhibitor therapy and drug resistance.
Bibliography:	istex:6919FFC33496324EE68CF8061CC240709BD1BC79 ark:/67375/TPS-GSLN0WVD-T Supported in part by NIH Grant R01 GM50579. ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0006-2960 1520-4995
DOI:	10.1021/bi9818927