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J. Biol. Chem., Vol. 281, Issue 47, 35717-35726, November 24, 2006

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A Conserved Subtilisin Protease Identified in Babesia divergens Merozoites^*

Estrella Montero, Luis Miguel Gonzalez, Marilis Rodriguez, Yelena Oksov, Michael J. Blackman^¶, and Cheryl A. Lobo¹

From the Department of Molecular Parasitology, Lindsley Kimball Research Institute, New York Blood Center, New York, New York 10021, the Division of Parasitology, Instituto de Salud Carlos III, Majadahonda, 28220 Madrid, Spain, and the ^¶Division of Parasitology, National Institute for Medical Research, Mill Hill, London NW7 1AA, United Kingdom

Invasion of erythrocytes is an integral part of the Babesia divergens life cycle. Serine proteases have been shown to play an important role in invasion by related Apicomplexan parasites such as the malaria parasite Plasmodium falciparum. Here we demonstrate the presence of two dominant serine proteases in asexual B. divergens using a biotinylated fluorophosphonate probe. One of these active serine proteases (p48) and its precursors were recognized by anti-PfSUB1 antibodies. These antibodies were used to clone the gene encoding a serine protease using a B. divergens cDNA library. BdSub-1 is a single copy gene with no introns. The deduced gene product (BdSUB-1) clearly belongs to the subtilisin superfamily and shows significant homology to Plasmodium subtilisins, with the highest degree of sequence identity around the four catalytic residues. Like subtilisin proteases in other Apicomplexan parasites, BdSUB-1 undergoes two steps of processing during activation in the secretory pathway being finally converted to an active form (p48). The mature protease is concentrated in merozoite dense granules, apical secretory organelles involved in erythrocyte invasion. Anti-PfSUB1 antibodies have a potent inhibitory effect on erythrocyte invasion by B. divergens merozoites in vitro. This report demonstrates conservation of the molecular machinery involved in erythrocyte invasion by these two Apicomplexan parasites and paves the way for a comparative analysis of other molecules that participate in this process in the two parasites.

Received for publication, May 8, 2006 , and in revised form, August 17, 2006.

^* This work was supported in part by Mohandas Narla (VP Fund, NY Blood Center) and the Quest Diagnostic Foundation. 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.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM /EBI Data Bank with accession number(s) DQ517294.

¹ To whom correspondence should be addressed: Dept. of Molecular Parasitology, Lindsley Kimball Research Institute, NY Blood Center, 310 E, 67th St., NY, NY, 10032. Tel.: 212-570-3415; Fax: 212-570-3415; E-mail: clobo{at}nybloodcenter.org.

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