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J. Biol. Chem., Vol. 278, Issue 48, 48169-48177, November 28, 2003

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Enzymic, Phylogenetic, and Structural Characterization of the Unusual Papain-like Protease Domain of Plasmodium falciparum SERA5^*

From the ^aThe Walter and Eliza Hall Institute of Medical Research, Melbourne, 1G Royal Parade, Parkville, Victoria 3050, Australia, the ^dDivision of Health Sciences and Nutrition, Commonwealth Scientific and Industrial Research Organisation, Melbourne, Victoria 3052, Australia, the ^fDepartment of Statistics, University of California, Berkeley, California 94720, the ^hJoint Proteomics Laboratory, Ludwig Institute for Cancer Research and the Walter and Eliza Hall Institute of Medical Research, Melbourne 3052, Australia, and the ⁱDepartment of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria 3800, Australia

Serine repeat antigen 5 (SERA5) is an abundant antigen of the human malaria parasite Plasmodium falciparum and is the most strongly expressed member of the nine-gene SERA family. It appears to be essential for the maintenance of the erythrocytic cycle, unlike a number of other members of this family, and has been implicated in parasite egress and/or erythrocyte invasion. All SERA proteins possess a central domain that has homology to papain except in the case of SERA5 (and some other SERAs), where the active site cysteine has been replaced with a serine. To investigate if this domain retains catalytic activity, we expressed, purified, and refolded a recombinant form of the SERA5 enzyme domain. This protein possessed chymotrypsin-like proteolytic activity as it processed substrates downstream of aromatic residues, and its activity was reversed by the serine protease inhibitor 3,4-diisocoumarin. Although all Plasmodium SERA enzyme domain sequences share considerable homology, phylogenetic studies revealed two distinct clusters across the genus, separated according to whether they possess an active site serine or cysteine. All Plasmodia appear to have at least one member of each group. Consistent with separate biological roles for members of these two clusters, molecular modeling studies revealed that SERA5 and SERA6 enzyme domains have dramatically different surface properties, although both have a characteristic papain-like fold, catalytic cleft, and an appropriately positioned catalytic triad. This study provides impetus for the examination of SERA5 as a target for antimalarial drug design.

Received for publication, June 25, 2003 , and in revised form, September 8, 2003.

^* This work was supported in part by the National Health and Medical Research Council (NHMRC) of Australia. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^c A recipient of an NHMRC postdoctoral award (Peter Doherty).

^e Present address: Swiss Institute for Experimental Cancer Research, CH-1066 Epalinges, Switzerland.

^g A recipient of an Australian Postgraduate Research Award.

^j An International Research Scholar of the Howard Hughes Medical Institute.

^b To whom correspondence may be addressed. Tel.: 61-3-9345-2555; Fax: 61-3-9347-0852; E-mail: hodder{at}wehi.edu.au (A. N. H.) and crabb{at}wehi.edu.au (B. S. C.).

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