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J. Biol. Chem., Vol. 280, Issue 52, 42515-42527, December 30, 2005

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Solution Structure of the Human Immunodeficiency Virus Type 1 p6 Protein^*

Torgils Fossen, Victor Wray, Karsten Bruns, Judhi Rachmat, Peter Henklein¶, Uwe Tessmer||, Annette Maczurek**, Patricia Klinger**, and Ulrich Schubert**1

From the Department of Structural Biology, Gesellschaft für Biotechnologische Forschung, D-38124 Braunschweig, Germany, the Department of Chemistry, University of Bergen, N-5007 Bergen, Norway, ^¶Institute of Biochemistry, Humboldt University, D-10115 Berlin, Germany, ^||Heinrich-Pette-Institute, D-20251 Hamburg, Germany, and ^**Institute of Clinical and Molecular Virology, University of Erlangen-Nürnberg, D-91054 Erlangen, Germany

The human immunodeficiency virus type 1 p6 protein represents a docking site for several cellular and viral binding factors and fulfills major roles in the formation of infectious viruses. To date, however, the structure of this 52-amino acid protein, by far the smallest lentiviral protein known, either in its mature form as free p6 or as the C-terminal part of the Pr55 Gag polyprotein has not been unraveled. We have explored the high resolution structure and folding of p6 by CD and NMR spectroscopy. Under membranous solution conditions, p6 can adopt a helix-flexible helix structure; a short helix-1 (amino acids 14–18) is connected to a pronounced helix-2 (amino acids 33–44) by a flexible hinge region. Thus, p6 can be subdivided into two distinct structural and functional domains; helix-2 perfectly defines the region that binds to the virus budding factor AIP-1/ALIX, indicating that this structure is required for interaction with the endosomal sorting complex required for transport. The PTAP motif at the N terminus, comprising the primary late assembly domain, which is crucial for interaction with another cellular budding factor, Tsg101, does not exhibit secondary structure. However, the adjacent helix-1 may play an indirect role in the specific complex formation between p6 and the binding groove in Tsg101. Moreover, binding studies by NMR demonstrate that helix-2, which also comprises the LXXLF motif required for incorporation of the human immunodeficiency virus type 1 accessory protein Vpr into budding virions, specifically interacts with the Vpr binding region, indicating that under the specific solution conditions used for structure analysis, p6 adopted a functional conformation.

Received for publication, July 7, 2005 , and in revised form, October 11, 2005.

^* This work was supported by German Human Genome Research Project Grant IE-S08T06 and by German Research Council Grant SFB 466-A11 (to U. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables 1–7 and Figs. 1–5.

¹ To whom correspondence should be addressed: Inst. for Clinical and Molecular Virology, University of Erlangen-Nürnberg, Schlossgarten 4, D-91054 Erlangen, Germany. Tel.: 49-9131-85-26182; Fax: 49-9131-85-22101; E-mail: ulrich.schubert{at}viro.med.uni-erlangen.de.

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