Integrin alpha-4 beta-1 (VLA-4) exofacial thiols (VLA-4 exofacial thiols)

Integrin alpha-4 beta-1 (VLA-4) exofacial thiols are specific cysteine residues located on the extracellular domain of the VLA-4 receptor that play a pivotal role in regulating its adhesive activity. These thiols are subject to redox-mediated modifications, such as thiol-disulfide exchange, which act as a molecular switch to transition the integrin from a low-affinity state to a high-affinity state [Chigaev et al., 2004]. This conformational change is essential for the binding of VLA-4 to its primary ligands, including Vascular Cell Adhesion Molecule-1 (VCAM-1) and fibronectin, facilitating the recruitment and extravasation of leukocytes into tissues [Lahav et al., 2003]. In inflammatory and autoimmune diseases like multiple sclerosis and Crohn's disease, this mechanism is exploited by the immune system to drive chronic inflammation and tissue damage [UniProt P13612]. Therapeutic strategies targeting VLA-4, such as the monoclonal antibody natalizumab or small molecule inhibitors like firategrast, aim to disrupt this adhesion process to treat these conditions [FDA, 2004]. However, the inhibition of VLA-4-mediated leukocyte trafficking carries a significant risk of progressive multifocal leukoencephalopathy (PML), a rare and often fatal viral infection of the brain caused by the reactivation of the JC virus [Tysabri Prescribing Information].

Other names

Alpha-4 beta-1 integrin exofacial thiolsCD49d/CD29 exofacial thiolsVLA-4 redox-sensitive cysteinesIntegrin alpha-4 beta-1 extracellular thiols

Inhibition of leukocyte adhesion by preventing the redox-dependent conformational transition of VLA-4 from a low-affinity to a high-affinity state through the modulation of exofacial cysteine residues [Chigaev et al., 2004; Lahav et al., 2003].