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Human CD4 Metastability Is a Function of the Allosteric Disulfide Bond in Domain 2
Gavin R Owen1, Jennifer A Channell2,3,4, V Trevor Forsyth2,3
1HIV Pathogenesis Research Unit, Department of Molecular Medicine and Haematology, Faculty of Health Sciences, University of the Witwatersrand , 7 York Road, Parktown, 2193, Johannesburg, South Africa.
Redox changes in the CD4 protein
Area of Science:
- Biochemistry
- Structural Biology
- Immunology
Background:
- CD4 is crucial for T-cell activation and HIV-1 entry.
- CD4 has four ectodomains (D1-D4) with disulfide bonds.
- The D2 domain's disulfide bond is allosteric and redox-sensitive.
Purpose of the Study:
- To investigate the biophysical effects of reducing CD4's disulfide bonds.
- To understand how redox state impacts CD4 structure and stability.
- To elucidate the role of the D2 allosteric disulfide in CD4 regulation.
Main Methods:
- Analysis of hydrodynamic volume, secondary structure, and thermal stability.
- Comparison of reduced and non-reduced forms of D1, D2, and two-domain CD4.
- Assessment of various redox isomers of CD4.
Main Results:
- Ablating the D2 allosteric disulfide caused structural collapse and increased stability.
- Ablating the D1 structural disulfide led to destabilizing rearrangements.
- CD4 exhibits disulfide-dependent metastability, particularly in D2.
Conclusions:
- CD4's function is regulated by the redox state of its D2 allosteric disulfide.
- Reduction of the D2 disulfide induces significant conformational changes.
- These redox-driven changes are critical for CD4's interactions with other proteins.
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