Calreticulin–integrin alpha 4 protein–protein interface (CRT–ITGA4 PPI)

The Calreticulin–integrin alpha 4 protein–protein interface is a critical regulatory junction that modulates the activation state and adhesive properties of the integrin alpha 4 subunit (ITGA4). Calreticulin, a calcium-binding chaperone, interacts with the conserved KXGFFKR motif in the cytoplasmic tail of ITGA4, facilitating 'inside-out' signaling that increases integrin affinity for ligands like VCAM-1 and MAdCAM-1 [1, 3]. This interaction is particularly significant in the recruitment of leukocytes to sites of inflammation, such as the intestinal mucosa in inflammatory bowel disease (IBD) [3, 4]. Therapeutic targeting of this interface with small molecules, such as ER-464195-01, aims to disrupt the complex to inhibit leukocyte infiltration and induce anti-inflammatory effects [3]. Furthermore, the interface plays a role in the translocation of calreticulin to the cell surface, where it serves as a pro-phagocytic signal in immunogenic cell death, linking it to both autoimmune and oncological applications [2, 5]. Disruption of this interface has been shown to ameliorate disease severity in animal models of colitis by suppressing the adhesiveness of T cells and neutrophils [3, 4]. The interface also couples calcium release from intracellular stores with extracellular calcium influx, further influencing cellular signaling pathways [1, 6].

Other names

Calreticulin-integrin alpha 4 interactionCRT-ITGA4 interactionCalreticulin-CD49d interfaceCRT-ITGA4 PPI

Inhibition of the protein-protein interaction between calreticulin and the integrin alpha 4 subunit to prevent integrin activation and leukocyte adhesion.