One functional switch mediates reversible and irreversible inactivation of a herpesvirus protease

Biochemistry
Anson M NomuraCharles S Craik

Abstract

Distinct mechanisms have evolved to regulate the function of proteolytic enzymes. Viral proteases in particular have developed novel regulatory mechanisms, presumably due to their comparatively rapid life cycles and responses to constant evolutionary pressure. Herpesviruses are a family of human pathogens that require a viral protease with a concentration-dependent zymogen activation involving folding of two alpha-helices and activation of the catalytic machinery, which results in formation of infectious virions. Kaposi's sarcoma-associated herpesvirus protease (KSHV Pr) is unique among the herpesvirus proteases in possessing an autolysis site in the dimer interface, which removes the carboxyl-terminal 27 amino acids comprising an alpha-helix adjacent to the active site. Truncation results in the irreversible loss of dimerization and concomitant inactivation. We characterized the conformational and functional differences between the active dimer, inactive monomer, and inactive truncated protease to determine the different protease regulatory mechanisms that control the KSHV lytic cycle. Circular dichroism revealed a loss of 31% alpha-helicity upon dimer dissociation. Comparison of the full-length and truncated monomers by NMR s...Continue Reading

References

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Citations

Jul 28, 2009·Nature Chemical Biology·Tina ShahianCharles S Craik
Jun 12, 2010·Molecular BioSystems·Aimee Shen
Jan 30, 2016·ChemMedChem·Jonathan E GableCharles S Craik
Jul 1, 2014·Biochemistry·Jonathan E GableCharles S Craik
Jul 5, 2011·Journal of Molecular Biology·Gregory M LeeCharles S Craik
Apr 25, 2008·Bioorganic & Medicinal Chemistry·Mark D Lim, Charles S Craik
Sep 18, 2007·Journal of Molecular Biology·Ana LazicCharles S Craik
Jul 11, 2014·Expert Opinion on Therapeutic Patents·Marcin Skoreński, Marcin Sieńczyk

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