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J. Biol. Chem., Vol. 278, Issue 44, 43188-43201, October 31, 2003

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Structural Characterization of the HIV-1 Vpr N Terminus

EVIDENCE OF cis/trans-PROLINE ISOMERISM^*

Karsten Bruns, Torgils Fossen¶, Victor Wray, Peter Henklein||, Uwe Tessmer, and Ulrich Schubert**

From the Department of Structural Biology, Gesellschaft für Biotechnologische Forschung, D-38124 Braunschweig, Germany, Heinrich-Pette-Institute, University of Hamburg, D-20251 Hamburg, Germany, ^¶Department of Chemistry, University of Bergen, 5007 Bergen, Norway, ^||Institute of Biochemistry, Humboldt University, D-10115 Berlin, Germany, the ^**Laboratory of Viral Diseases, NIAID, National Institutes of Health, Bethesda, Maryland 20892, and the Institute for Clinical and Molecular Virology, University of Erlangen-Nüruberg, D-91054 Erlangen, Germany

The 96-residue human immunodeficiency virus (HIV) accessory protein Vpr serves manifold functions in the retroviral life cycle including augmentation of viral replication in non-dividing host cells, induction of G₂ cell cycle arrest, and modulation of HIV-induced apoptosis. Using a combination of dynamic light scattering, circular dichroism, and NMR spectroscopy the N terminus of Vpr is shown to be a unique domain of the molecule that behaves differently from the C-terminal domain in terms of self-association and secondary structure folding. Interestingly, the four highly conserved proline residues in the N terminus are predicted to have a high propensity for cis/trans isomerism. Thus the high resolution structure and folding of a synthetic N-terminal peptide (Vpr^1–40) and smaller fragments thereof have been investigated. ¹H NMR data indicate Vpr^1–40 possesses helical structure between residues 17–32, and for the first time, this helix, which is bound by proline residues, was observed even in aqueous solution devoid of any detergent supplements. In addition, NMR data revealed that all of the proline residues undergo a cis/ trans isomerism to such an extent that 40% of all Vpr molecules possess at least one proline in a cis conformation. This phenomenon of cis/trans isomerism, which is unprecedented for HIV-1 Vpr, not only provides an explanation for the molecular heterogeneity observed in the full-length molecule but also indicates that in vivo the folding and function of Vpr should depend on a cis/trans-proline isomerase activity, particularly as two of the proline residues in positions 14 and 35 show considerable amounts of cis isomers. This prediction correlates well with our recent observation (Zander, K., Sherman, M. P., Tessmer, U., Bruns, K., Wray, V., Prechtel, A. T., Schubert, E., Henklein, P., Luban, J., Neidleman, J., Greene, W. C., and Schubert, U. (2003) J. Biol. Chem. 278, 43170–43181) of a functional interaction between the major cellular isomerase cyclophilin A and Vpr, both of which are incorporated into HIV-1 virions.

Received for publication, May 23, 2003

^* This work was supported in part by National Institutes of Health R01 Grant DK59537-1, by Grant SFB 466-A11, by a Heisenberg grant from the Deutsche Forschungsgemeinschaft, by German Human Genome Research Project Grant IE-S08T06 (to U. S.), and by a fellowship from the Norwegian Research Council (to T. F.). 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 Material.

To whom correspondence should be addressed: Inst. for Clinical and Molecular Virology, University of Erlangen-Nürnberg, Schlossgarten 4, Erlangen 91054, Germany. Tel.: 49-9131-85-26182; Fax: 49-9131-85-22101; E-mail: ulrich.schubert{at}viro.med.uni-erlangen.

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