Disulfide exchange in CD4

Building Better Chimeric Antigen Receptors for Adoptive T Cell Therapy

“…Since the first reported use of the CD4 transmembrane domain was published in 1998 [30] it has been extensively used in preclinical studies and clinical trials conducted by the group of Michael C. Jensen (City of Hope National Medical Center, USA). Immunoblot analysis of their anti-CD20 scFv.hIgG.CD4.CD3 CAR demonstrated a homodimeric receptor; however, dimerisation would be mediated by the IgG hinge region rather than the highly truncated CD4 region used in this receptor as pairing of wild-type CD4 on the cell surface occurs through a complex interaction between components of the extracellular domain [69][70][71]. Indeed, Fitzer-Attas et al [68] found that chimeric receptors with the CD4 transmembrane domain alone, and no extracellular spacer, failed to form dimers under nonreducing conditions.…”

Single molecule force spectroscopy discovers mechanochemical switches in biology: The case of the disulfide bond

“…In the case of the CD-4 receptor both oxidised and reduced forms of the molecule co-exist in equilibrium on the T-cell surface, and T-cell activation leads to a shift to the reduced form. This suggests a definite but still unknown functional role of the disulfide reduction in the CD-4 receptor [16] and indicate that the reversible cleavage of disulfide bonds in extracellular proteins may be an important tool for the regulation of their function. CD-4 disulfide reduction has been shown to block HIV infection [19].…”

“…It has been proved that the CD4 receptor activity is regulated by disulfide reduction [16] (see Section 2), and that the mechanical properties of a cell adhesion molecule (CAM) can be modulated by mean of its disulfide bonds [58]. The vascular cell adhesion molecules (VCAMs) and CD2 [67] are two other examples of the many cell adhesion molecules that contain disulfide bonds in their structures.…”

“…Is the disulfide bond cleavage a mechanism for protein function control? Extracellular regulation by disulfide cleavage has been specifically demonstrated in secreted proteins like thrombospondin-1 [13], von Willebrand factor (vWF) [14] and plasmin [15], in cell-surface receptors including CD-4 T cell receptor [16], integrins [17] and the HIV gp120 [18]. The functional effects of this regulation are different and not always clear.…”

The interplay between chemistry and mechanics in the transduction of a mechanical signal into a biochemical function

“…However this static view of the function of disulfide bonds has been challenged since the mid1990s by a steady increase of evidence for extracellular regulation due to disulfide cleavage. Examples include secreted proteins like thrombospondin-1 [122], von Willebrand factor [123,124] and plasmin [125], and cell surface receptors like the CD-4 T-cell receptor [126], integrins [127,128] and the HIV protein gp120 [129]. Extracellular redox regulation has also been suggested as essential in activation of Gprotein coupled receptors [130].…”