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J. Biol. Chem., Vol. 283, Issue 6, 3584-3593, February 8, 2008

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Structure of a Glycosylphosphatidylinositol-anchored Domain from a Trypanosome Variant Surface Glycoprotein^*

From the Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom

The cell surface of African trypanosomes is covered by a densely packed monolayer of a single protein, the variant surface glycoprotein (VSG). The VSG protects the trypanosome cell surface from effector molecules of the host immune system and is the mediator of antigenic variation. The sequence divergence between VSGs that is necessary for antigenic variation can only occur within the constraints imposed by the structural features necessary to form the monolayer barrier. Here, the structures of the two domains that together comprise the C-terminal di-domain of VSG ILTat1.24 have been determined. The first domain has a structure similar to the single C-terminal domain of VSG MITat1.2 and provides proof of structural conservation in VSG C-terminal domains complementing the conservation of structure present in the N-terminal domain. The second domain, although based on the same fold, is a minimized version missing several structural features. The structure of the second domain contains the C-terminal residue that in the native VSG is attached to a glycosylphosphatidylinositol (GPI) anchor that retains the VSG on the external face of the plasma membrane. The solution structures of this domain and a VSG GPI glycan have been combined to produce the first structure-based model of a GPI-anchored protein. The model suggests that the core glycan of the GPI anchor lies in a groove on the surface of the domain and that there is a close association between the GPI glycan and protein. More widely, the GPI glycan may be an integral part of the structure of other GPI-anchored proteins.

Received for publication, July 27, 2007 , and in revised form, October 16, 2007.

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

^* This work was supported by the Wellcome Trust. 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 on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

² Present address: Faculty of Veterinary Medicine, Universiti Putra Malaysia, 43400 UPM, Serdang, Selangor, Malaysia.

¹ To whom correspondence may be addressed. Present address: Dept. of Microbiology and Genetics, TU Darmstadt, Schnittspahnstr. 10, 64287 Darmstadt, Germany. Tel.: 49-6151-165154; Fax: 49-6151-167440; E-mail: jones{at}bio.tu-darmstadt.de.

³ To whom correspondence may be addressed: Dept. of Biochemistry, University of Cambridge, 80 Tennis Court Rd., Cambridge CB2 1GA, UK. Tel.: 44-1223-333683; Fax: 44-1223-766002; E-mail: mc115{at}cam.ac.uk.

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