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J Biol Chem, Vol. 274, Issue 21, 14918-14925, May 21, 1999

A Human RNA Viral Cysteine Proteinase That Depends upon a Unique Zn²⁺-binding Finger Connecting the Two Domains of a Papain-like Fold

Jens Herold, Stuart G. Siddell, and Alexander E. Gorbalenya^¶**

From the  Institute of Virology and Immunology, University of Würzburg, Versbacher Strasse 7, 97078 Würzburg, Germany, the ^¶ Advanced Biomedical Computing Center, SAIC/NCI-Frederick Cancer Research and Development Center, National Institutes of Health, Frederick, Maryland 21702-1201,  Leiden University Medical Center, AZL P4-22, P.O. BOX 9600, 2300RC Leiden, The Netherlands, and the ^** M. P. Chumakov Institute of Poliomyelitis and Viral Encephalitides, Russian Academy of Medical Sciences, 142782 Moscow Region, Russia

A cysteine proteinase, papain-like proteinase (PL1pro), of the human coronavirus 229E (HCoV) regulates the expression of the replicase polyproteins, pp1a and ppa1ab, by cleavage between Gly¹¹¹ and Asn¹¹², far upstream of its own catalytic residue Cys¹⁰⁵⁴. In this report, using bioinformatics tools, we predict that, unlike its distant cellular homologues, HCoV PL1pro and its coronaviral relatives have a poorly conserved Zn²⁺ finger connecting the left and right hand domains of a papain-like fold. Optical emission spectrometry has been used to confirm the presence of Zn²⁺ in a purified and proteolytically active form of the HCoV PL1pro fused with the Escherichia coli maltose-binding protein. In denaturation/renaturation experiments using the recombinant protein, its activity was shown to be strongly dependent upon Zn²⁺, which could be partly substituted by Co²⁺ during renaturation. The reconstituted, Zn²⁺-containing PL1pro was not sensitive to 1,10-phenanthroline, and the Zn²⁺-depleted protein was not reactivated by adding Zn²⁺ after renaturation. Consistent with the proposed essential structural role of Zn²⁺, PL1pro was selectively inactivated by mutations in the Zn²⁺ finger, including replacements of any of four conserved Cys residues predicted to co-ordinate Zn²⁺. The unique domain organization of HCoV PL1pro provides a potential framework for regulatory processes and may be indicative of a nonproteolytic activity of this enzyme.

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