ArticleThe Journal of biological chemistry2014
Disulfide reduction in CD4 domain 1 or 2 is essential for interaction with HIV glycoprotein 120 (gp120), which impairs thioredoxin-driven CD4 dimerization.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed.
- Targeting protein disulfide isomerase with the flavonoid isoquercetin to improve hypercoagulability in advanced cancer.JCI insight · 2019Trial
- Chimeric antigen receptor T (CAR-T) cell therapy in non-oncological diseases.Signal transduction and targeted therapy · 2026Review
- Inflammation and RONS Dysregulation by Redox Enzymes as Mechanistic Links in HIV-1-Cancer Comorbidity.Pathogens (Basel, Switzerland) · 2026Review
- Conformational activation and disulfide exchange in HIV-1 Env induce cell-free lytic/fusogenic transformation and enhance infection.Journal of virology · 2025Article
- Redox regulation of HIV-1: the thioredoxin pathway, oxidative metabolism, and latency control.Frontiers in physiology · 2025Review
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- Article
- Selenium-More than Just a Fortuitous Sulfur Substitute in Redox Biology.Molecules (Basel, Switzerland) · 2023Review
- Extracellular domain, hinge, and transmembrane determinants affecting surface CD4 expression of a novel anti-HIV chimeric antigen receptor (CAR) construct.bioRxiv : the preprint server for biology · 2023Article
- Defining the Cell Surface Cysteinome using Two-step Enrichment Proteomics.bioRxiv : the preprint server for biology · 2023Article
- A proximity-based in silico approach to identify redox-labile disulfide bonds: The example of FVIII.PloS one · 2022Article
- Thiol Modifications in the Extracellular Space-Key Proteins in Inflammation and Viral Infection.Frontiers in immunology · 2022Review
- Pathological consequences of the unfolded protein response and downstream protein disulphide isomerases in pulmonary viral infection and disease.Journal of biochemistry · 2020Review
- Article
- Engineering and characterising a novel, highly potent bispecific antibody iMab-CAP256 that targets HIV-1.Retrovirology · 2019Article
- Inhibition of the thioredoxin system by PX-12 (1-methylpropyl 2-imidazolyl disulfide) impedes HIV-1 infection in TZM-bl cells.Scientific reports · 2019Article
- Galectin-9 binds to O-glycans on protein disulfide isomerase.Glycobiology · 2017Article
- From structure to redox: The diverse functional roles of disulfides and implications in disease.Proteomics · 2017Review
- High thioredoxin-1 levels in rheumatoid arthritis patients diminish binding and signalling of the monoclonal antibody Tregalizumab.Clinical & translational immunology · 2016Article
- Thiol-Disulfide Exchange Reactions in the Mammalian Extracellular Environment.Annual review of chemical and biomolecular engineering · 2016Review
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5 authors.
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Abstract
Human CD4 is a membrane-bound glycoprotein expressed on the surface of certain leukocytes, where it plays a key role in the activation of immunostimulatory T cells and acts as the primary receptor for human immunodeficiency virus (HIV) glycoprotein (gp120). Although growing evidence suggests that redox exchange reactions involving CD4 disulfides, potentially catalyzed by cell surface-secreted oxidoreductases such as thioredoxin (Trx) and protein disulfide isomerase, play an essential role in regulating the activity of CD4, their mechanism(s) and biological utility remain incompletely understood. To gain more insights in this regard, we generated a panel of recombinant 2-domain CD4 proteins (2dCD4), including wild-type and Cys/Ala variants, and used these to show that while protein disulfide isomerase has little capacity for 2dCD4 reduction, Trx reduces 2dCD4 highly efficiently, catalyzing the formation of conformationally distinct monomeric 2dCD4 isomers, and a stable, disulfide-linked 2dCD4 dimer. Moreover, we show that HIV gp120 is incapable of binding a fully oxidized, monomeric 2dCD4 in which both domain 1 and 2 disulfides are intact, but binds robustly to reduced counterparts that are the ostensible products of Trx-mediated isomerization. Finally, we demonstrate that Trx-driven dimerization of CD4, a process believed to be critical for the establishment of functional MHCII-TCR-CD4 antigen presentation complexes, is impaired when CD4 is bound to gp120. These observations reinforce the importance of cell surface redox activity for HIV entry and posit the intriguing possibility that one of the many pathogenic effects of HIV may be related to gp120-mediated inhibition of oxidoreductive CD4 isomerization.
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