Platelet integrin αIIbβ3: activation mechanisms

Abstract

Summary. Integrin αIIbβ3 plays a critical role in platelet aggregation, a central response in hemostasis and thrombosis. This function of αIIbβ3 depends upon a transition from a resting to an activated state such that it acquires the capacity to bind soluble ligands. Diverse platelet agonists alter the cytoplasmic domain of αIIbβ3 and initiate a conformational change that traverses the transmembrane region and ultimately triggers rearrangements in the extracellular domain to permit ligand binding. The membrane‐proximal regions of αIIb and β3 cytoplasmic tails, together with the transmembrane segments of the subunits, contact each other to form a complex which restrains the integrin in the resting state. It is unclasping of this complex that induces integrin activation. This clasping/unclasping process is influenced by multiple cytoplasmic tail binding partners. Among them, talin appears to be a critical trigger of αIIbβ3 activation, but other binding partners, which function as activators or suppressors, are likely to act as co‐regulators of integrin activation.

Subcellular Localization of Talin Is Regulated by Inter-domain Interactions

“…Initially, 15 N-labeled F2F3 was screened against the five large fragments of talin Tln1(1-433), Tln1(434 -911), Tln1(913-1653), Tln1(1655-2294), and Tln1(2300 -2541).…”

“…In platelets, cells in which integrin affinity is tightly regulated, full-length (FL) 2 talin remains in the cytosol until the cells are stimulated by agonists, resulting in talin redistribution to the plasma membrane (14) and increased integrin affinity (15,16). Furthermore, recent studies using model cellular systems have established that talin is cytosolic until it interacts with an activated Rap1-RIAM complex that recruits FL talin to the plasma membrane (17)(18)(19).…”

Kindlin supports platelet integrin αIIbβ3 activation by interacting with paxillin

“…The activation states of integrins are tightly controlled by interactions between α-and β-subunits at both the membrane-proximal cytoplasmic tails (CTs) and the transmembrane domains (Vinogradova et al, 2002;Yang et al, 2009;Zhu et al, 2009). Integrin conformational changes toward active states can be triggered by the binding of cytoplasmic integrin activators to the integrin β CTs (Liu et al, 2000;Ma et al, 2007;Moser et al, 2009b;Qin et al, 2004). Among many integrin β CT binding proteins, the talin head domain (TH) and the kindlin family members are essentially required to induce integrin activation (Moser et al, 2009b;Tadokoro et al, 2003).…”

The Tetraspanin CD9 Localizes to Platelet-Platelet Contacts and Regulates Thrombus Stability

“…More than 20 proteins have been identified as binding partners, most prominently talin (which links the integrin to the actin cytoskeleton and is critical in integrin-mediated focal adhesion formation) (Burridge 1996, Rees 1990). The cytoplasmic domains can also directly interact with the cytoskeletal proteins myosin, skelemin, filamin, α-actinin, and F-actin; the adaptor/signaling proteins paxillin, Shc, and Grb 2; the protein kinases/phosphatases Src, Csk, Syk, ILK, FAK, and PP1c; and BiP, Calreticulin, and β3-endonexin (Ma 2007). αIIbβ3 can also bind with the transmembrane proteins CD36, CD47/IAP, CD98, and CD31, as well as the tetraspanins CD9, CD63, and CD151, although these interactions likely involve interactions with the transmembrane and extracellular domains (Ma 2007).…”

“…β3 is composed of 762 amino acids, with an extracellular domain consisting of an A domain, plexin/semaphorin/integrin domain, four EGF domains, and a membrane-proximal βTD domain (Xiong 2001). The extracellular domains of the α and β subunits combine to form an ellipsoid -head‖ consisting of the β-propeller and A-domain, and two tails (Ma 2007). The transmembrane domains of each subunit form alpha helices that are believed to interact when the integrin is in a resting conformation (Adair 2002, Gottschalk 2005.…”