University Of Tasmania
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Disulfide bond that constrains the HIV-1 gp120 V3 domain is cleaved by thioredoxin

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posted on 2023-05-19, 16:16 authored by Iman AzimiIman Azimi, Matthias, LJ, Center, RJ, Wong, JW, Hogg, PJ
A functional disulfide bond in both the HIV envelope glycoprotein, gp120, and its immune cell receptor, CD4, is involved in viral entry, and compounds that block cleavage of the disulfide bond in these proteins inhibit HIV entry and infection. The disulfide bonds in both proteins are cleaved at the cell surface by the small redox protein, thioredoxin. The target gp120 disulfide and its mechanism of cleavage were determined using a thioredoxin kinetic trapping mutant and mass spectrometry. A single disulfide bond was cleaved in isolated and cell surface gp120, but not the gp160 precursor, and the extent of the reaction was enhanced when gp120 was bound to CD4. The Cys(32) sulfur ion of thioredoxin attacks the Cys(296) sulfur ion of the gp120 V3 domain Cys(296)-Cys(331) disulfide bond, cleaving the bond. Considering that V3 sequences largely determine the chemokine receptor preference of HIV, we propose that cleavage of the V3 domain disulfide, which is facilitated by CD4 binding, regulates chemokine receptor binding. There are 20 possible disulfide bond configurations, and, notably, the V3 domain disulfide has the same unusual -RHStaple configuration as the functional disulfide bond cleaved in CD4.


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Journal of Biological Chemistry










School of Pharmacy and Pharmacology


Amer Soc Biochemistry Molecular Biology Inc

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9650 Rockville Pike, Bethesda, USA, Md, 20814-3996

Rights statement

This research was originally published in the Journal of Biological Chemistry. Iman Azimi, Lisa J. Matthias, Rob J. Center, Jason W.H. Wong and Philip J. Hogg. Disulfide bond that constrains the HIV-1 gp120 V3 domain is cleaved by thioredoxin. J. Biol. Chem. 2010; 285:p.40072-40080 © the American Society for Biochemistry and Molecular Biology

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