Structural basis of blocking integrin activation and deactivation for anti-inflammation

Abstract

Integrins mediate leukocyte accumulation to the sites of inflammation, thereby enhancing their potential as an important therapeutic target for inflammatory disorders. Integrin activation triggered by inflammatory mediators or signaling pathway is a key step to initiate leukocyte migration to inflamed tissues; however, an appropriately regulated integrin deactivation is indispensable for maintaining productive leukocyte migration. While typical integrin antagonists that block integrin activation target the initiation of leukocyte migration, a novel class of experimental compounds has been designed to block integrin deactivation, thereby perturbing the progression of cell migration. Current review discusses the mechanisms by which integrin is activated and subsequently deactivated by focusing on its structure-function relationship.

Fig. 1

Different integrin conformations. a Bent conformation containing the closed headpiece (with low-affinity I domain). b Extended conformation containing the closed headpiece (with intermediate-affinity I-domain). c Extended conformation containing the open headpiece (with the high-affinity I domain). I-EGF, integrin-epidermal growth factor; PSI, plexin/semaphorin/integrin; TM, transmembrane

Fig. 2

Integrin activator talin and co-activator kindlin. a The auto-inhibition of talin is release either by phosphorylation or partial proteolysis. b Recruitment of talin to integrin is mediated by binding Rap1-RIAM complex. c Binding of talin to the integrin triggers the dissociation of the α/β integrin cytoplasmic domains, thereby inducing active extended conformation. d Kindlin acts as a co-activator to stabilize integrin-mediated cell adhesion that involves multivalent ligand binding

Fig. 3

Structural components to stabilize inactive integrin conformation. a The cytoplasmic salt bridge is formed between the arginine residue in the α subunit and the glutamate residue in the β subunit, thereby clasping the α/β integrin cytoplasmic tails. A mutation to disrupt the salt bridge results in promoting the cytoplasmic dissociation, thereby inducing integrin activation. b A conserved isoleucine at the α I domain C-terminal helix acts as a ratchet to stabilize the inactive conformation. A downward shift of the C-terminal helix is mediated by an interdomain interaction by the β I domain (also known as I-like domain). c Ca²⁺ binding site ADMIDAS in the β I domain favors the inactive low-affinity integrin headpiece conformation. A mutation to disrupt the Ca²⁺ binding site induces the constitutively active conformation by facilitating the conformational swing out of the hybrid domain