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Vol. 19, Issue 10, 4298-4309, October 2008

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Only Five of 10 Strictly Conserved Disulfide Bonds Are Essential for Folding and Eight for Function of the HIV-1 Envelope Glycoprotein

Eelco van Anken^*,,, Rogier W. Sanders^,, I. Marije Liscaljet^*,,||, Aafke Land^*, Ilja Bontjer, Sonja Tillemans^*,¶, Alexey A. Nabatov, William A. Paxton, Ben Berkhout, and Ineke Braakman^*

*Cellular Protein Chemistry, Bijvoet Center for Biomolecular Research, Faculty of Science, Utrecht University, 3584 CH Utrecht, The Netherlands; and Department of Human Retrovirology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands

Submitted December 26, 2007; Revised July 2, 2008; Accepted July 10, 2008
Monitoring Editor: Reid Gilmore

Protein folding in the endoplasmic reticulum goes hand in hand with disulfide bond formation, and disulfide bonds are considered key structural elements for a protein's folding and function. We used the HIV-1 Envelope glycoprotein to examine in detail the importance of its 10 completely conserved disulfide bonds. We systematically mutated the cysteines in its ectodomain, assayed the mutants for oxidative folding, transport, and incorporation into the virus, and tested fitness of mutant viruses. We found that the protein was remarkably tolerant toward manipulation of its disulfide-bonded structure. Five of 10 disulfide bonds were dispensable for folding. Two of these were even expendable for viral replication in cell culture, indicating that the relevance of these disulfide bonds becomes manifest only during natural infection. Our findings refine old paradigms on the importance of disulfide bonds for proteins.

These authors contributed equally to this work.

Present addresses: Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158-2517;

^|| Crucell, PO Box 2048, 2301 CA Leiden, The Netherlands;

^¶ Department of Immunology, Erasmus MC, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands.

Address correspondence to: Ineke Braakman (I.Braakman{at}uu.nl)

Abbreviations used: endoH, endoglycosidase H; Env, envelope glycoprotein; ER, endoplasmic reticulum; HIV, human immunodeficiency virus; PBMC, peripheral blood mononuclear cell.

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