Functional characterization of the protease of human endogenous retrovirus, K10: can it complement HIV-1 protease?

Biochemistry. 1998 Dec 8;37(49):17137-44. doi: 10.1021/bi9818927.


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 Kd of 50 microM. 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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Aspartic Acid Endopeptidases / chemistry*
  • Aspartic Acid Endopeptidases / metabolism
  • Binding Sites
  • Capsid / metabolism
  • Catalysis
  • Dimerization
  • Endogenous Retroviruses / enzymology*
  • Enzyme Stability
  • Gene Products, gag / metabolism
  • HIV Antigens / metabolism
  • HIV Protease / chemistry*
  • HIV Protease / metabolism
  • Humans
  • Hydrogen-Ion Concentration
  • Models, Molecular
  • Molecular Sequence Data
  • Molecular Weight
  • Protein Processing, Post-Translational
  • Structure-Activity Relationship
  • Viral Proteins*
  • gag Gene Products, Human Immunodeficiency Virus


  • Gene Products, gag
  • HIV Antigens
  • Viral Proteins
  • gag Gene Products, Human Immunodeficiency Virus
  • p17 protein, Human Immunodeficiency Virus Type 1
  • Aspartic Acid Endopeptidases
  • HIV Protease