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Vol. 19, Issue 11, 4707-4716, November 2008

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Evolution Rescues Folding of Human Immunodeficiency Virus-1 Envelope Glycoprotein GP120 Lacking a Conserved Disulfide Bond

Rogier W. Sanders^*,, Shang-Te D. Hsu^,,, Eelco van Anken^||,,¶, I. Marije Liscaljet^||,#, Martijn Dankers^*, Ilja Bontjer^*, Aafke Land^||, Ineke Braakman^||, Alexandre M.J.J. Bonvin, and Ben Berkhout^*

*Laboratory of Experimental Virology, Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; and NMR Spectroscopy and ^||Cellular Protein Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, 3584 CH Utrecht, The Netherlands

Submitted July 2, 2008; Accepted August 19, 2008
Monitoring Editor: Reid Gilmore

The majority of eukaryotic secretory and membrane proteins contain disulfide bonds, which are strongly conserved within protein families because of their crucial role in folding or function. The exact role of these disulfide bonds during folding is unclear. Using virus-driven evolution we generated a viral glycoprotein variant, which is functional despite the lack of an absolutely conserved disulfide bond that links two antiparallel β-strands in a six-stranded β-barrel. Molecular dynamics simulations revealed that improved hydrogen bonding and side chain packing led to stabilization of the β-barrel fold, implying that β-sheet preference codirects glycoprotein folding in vivo. Our results show that the interactions between two β-strands that are important for the formation and/or integrity of the β-barrel can be supported by either a disulfide bond or β-sheet favoring residues.

These authors contributed equally to this work.

Present addresses: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom;

^¶ Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158-2517;

^# Crucell, P.O. Box 2048, 2301 Leiden, The Netherlands.

Address correspondence to: Rogier W. Sanders (r.w.sanders{at}amc.uva.nl)