TAILIEUCHUNG - Báo cáo khoa học: A ribonuclease zymogen activated by the NS3 protease of the hepatitis C virus

Translating proteases as inactive precursors, or zymogens, protects cells from the potentially lethal action of unregulated proteolytic activity. Here, we impose this strategy on bovine pancreatic ribonuclease (RNase A) by creating a zymogen in which quiescent ribonucleolytic activity is activated by the NS3 protease of the hepatitis C virus. | ỊFEBS Journal A ribonuclease zymogen activated by the NS3 protease of the hepatitis C virus R. J. Johnson1 Shawn R. Lin1 and Ronald T. Raines1 2 1 Department of Biochemistry University of Wisconsin-Madison Madison WI USA 2 Department of Chemistry University of Wisconsin-Madison Madison WI USA Keywords circular permutation ribonuclease A ribonuclease inhibitor RNA virus Correspondence R. T. Raines Department of Biochemistry University of Wisconsin-Madison 433 Babcock Drive Madison WI 53706-1544 USA Fax 1 608 262 3453 Tel 1 608 262 8588 E-mail raines@ Received 26 August 2006 revised 9 October 2006 accepted 12 October 2006 doi Translating proteases as inactive precursors or zymogens protects cells from the potentially lethal action of unregulated proteolytic activity. Here we impose this strategy on bovine pancreatic ribonuclease RNase A by creating a zymogen in which quiescent ribonucleolytic activity is activated by the NS3 protease of the hepatitis C virus. Connecting the N-terminus and C-terminus of RNase A with a 14-residue linker was found to diminish its ribonucleolytic activity by both occluding an RNA substrate and dislocating active-site residues which are devices used by natural zymogens. After cleavage of the linker by the NS3 protease the ribonucleolytic activity of the RNase A zymogen increased 105-fold. Both before and after activation the RNase A zymogen displayed high conformational stability and evasion of the endogenous ribonuclease inhibitor protein of the mammalian cytosol. Thus the creation of ribonuclease zymogens provides a means to control ribonucleolytic activity and has the potential to provide a new class of antiviral chemotherapeutic agents. Proteolysis is an essential biological activity that requires tight regulation 1 2 . One strategy employed by cells to control proteolysis is to encode proteolytic enzymes as inactive precursors zymogens 3 . Zymogens are translated with N-terminal .

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