One common method of integrin inactivation involves conformational changes within the integrin molecule itself. Integrins exist in an inactive, bent conformation and an active, extended conformation. The transition between these states is regulated by intracellular signaling pathways and can be influenced by factors such as divalent cations, particularly magnesium and manganese. Inactivation can occur when integrins revert to their bent, inactive conformation, reducing their affinity for ligands.
Another mechanism of integrin inactivation involves the binding of inhibitory molecules. For example, certain antibodies and small molecule inhibitors can bind to integrins and prevent them from adopting their active conformation. Additionally, some proteins, such as the cytoplasmic tail-associated protein kindlin, can regulate integrin activity by modulating the interaction between the integrin's cytoplasmic domains and the cytoskeleton.
Integrin inactivation can also be achieved through post-translational modifications, such as phosphorylation and ubiquitination. These modifications can alter integrin conformation, stability, and interactions with other proteins, leading to reduced integrin activity. Furthermore, integrin inactivation can occur as a result of proteolytic cleavage, which can remove critical domains required for integrin function.
In pathological contexts, integrin inactivation can contribute to diseases such as cancer and autoimmune disorders. For instance, reduced integrin activity can impair immune cell adhesion and migration, leading to compromised immune surveillance and increased susceptibility to infections. Conversely, excessive integrin inactivation can also promote tumor metastasis by facilitating cancer cell detachment from the primary tumor site and dissemination to distant organs.