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J. Biol. Chem., Vol. 283, Issue 35, 24077-24088, August 29, 2008

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Crystal Structure of Soluble Domain of Malaria Sporozoite Protein UIS3 in Complex with Lipid^*

From the Structural and Computational Biology Group, International Centre for Genetic Engineering and Biotechnology, New Delhi 110067, India

Malaria parasite UIS3 (up-regulated in infective sporozoites gene 3) is essential for sporozoite development in infected hepatocytes. UIS3 encodes for a membrane protein that is localized to the parasite parasitophorous vacuolar membrane in infected hepatocytes. We describe here 2.5-Å resolution crystal structure of Plasmodium falciparum UIS3 soluble domain (PfUIS3^130-229) in complex with the lipid phosphatidylethanolamine (PE). PfUIS3^130-229 is a novel, compact, and all -helical structure bound to one molecule of PE. The PfUIS3^130-229-PE complex structure reveals a novel binding site with specific interactions between PfUIS3^130-229 and the PE head group. One acyl chain of PE wraps around part of PfUIS3^130-229 and docks onto a hydrophobic channel. We additionally provide new structural and biochemical evidence of PfUIS3^130-229 interactions with lipids (phosphatidylethanolamine), with phospholipid liposomes, and with the human liver fatty acid-binding protein. The direct interaction of PfUIS3^130-229 with liver fatty acid-binding protein most likely provides the parasite with a conduit for importing essential fatty acids/lipids. Therefore, our analyses have implications for lipid transport into the parasite during the rapid growth phases of sporozoites. Given that PfUIS3 is essential for establishment of liver stage infection by P. falciparum, our data provide a new target for abrogating parasite development within liver cells before typical symptoms of malaria can manifest.

Received for publication, March 11, 2008 , and in revised form, June 23, 2008.

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The atomic coordinates and structure factors (code 2vwa) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work is supported by a Department of Biotechnology (Government of India) career development award (to A. S.). 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.

¹ Supported by a University Grants Commission Government of India fellowship.

² Supported by the Wellcome Trust.

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³ International Wellcome Trust Senior Research Fellow in Biomedical Sciences. To whom correspondence should be addressed: International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Road, New Delhi 110067, India. Tel./Fax: 91-11-26741731; E-mail: amit.icgeb{at}gmail.com.

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