Crystal Structure of the Extracellular Segment of Integrin αVβ3

Abstract

Integrins are αβ heterodimeric receptors that mediate divalent cation-dependent cell-cell and cellmatrix adhesion through tightly regulated interactions with ligands. We have solved the crystal structure of the extracellular portion of integrin αVβ3 at 3.1 Å resolution. Its 12 domains assemble into an ovoid "head" and two "tails." In the crystal, αVβ3 is severely bent at a defined region in its tails, reflecting an unusual flexibility that may be linked to integrin regulation. The main inter-subunit interface lies within the head, between a seven-bladed β-propeller from αV and an A domain from β3, and bears a striking resemblance to the Gα/Gβ interface in G proteins. A metal ion-dependent adhesion site (MIDAS) in the βA domain is positioned to participate in a ligand-binding interface formed of loops from the propeller and βA domains. MIDAS lies adjacent to a calcium-binding site with a potential regulatory function.Integrins are large heterodimeric cell surface receptors found in many animal species ranging from sponges to mammals [reviewed in (1)]. These receptors are involved in fundamental cellular processes such as attachment, migration, proliferation, differentiation, and survival. Integrins also contribute to the initiation and/or progression of many common diseases including neoplasia, tumor metastasis, immune dysfunction, ischemia-reperfusion injury, viral infections, osteoporosis, and coagulopathies [reviewed in (2,3)]. An integrin is ~280 Å long and consists of one α (150 to 180 kD) and one β (~90 kD) subunit, both of which are type I membrane proteins. Eighteen α and eight β mammalian subunits are known, which assemble noncovalently into 24 different heterodimers. Contacts between the α and β subunits primarily involve their NH 2 -terminal halves [reviewed in (1)], which together form a globular head; the remaining portions form two rod-shaped tails (4-7) that span the plasma membrane.Like other receptors, integrins transmit signals to the cell interior (so-called "outside-in" signaling), which regulate organization of the cytoskeleton, activate kinase signaling cascades, and modulate the cell cycle and gene expression [reviewed in (8)]. Unlike other receptors, however, ligand binding with integrins is not generally constitutive but is regulated to reflect the activation state of the cell. This "inside-out" regulation of integrin affinity protects the host

Multifocal structure of the T cell - dendritic cell synapse

“…The possibility that the distance of interaction between LFA-1 and ICAM-1 could be smaller than previously expected has recently been questioned, on the basis of crystallographic data [17] (see "Discussion"). As our data show that in T-DC synapses, the cleft size is rarely close to 40-45 nm, we asked whether LFA-1-ICAM-1 interactions could take place when the synaptic cleft was narrower than that.…”

Structural and mechanical functions of integrins

“…1). When present, the αI domain in α-subunits forms the major ligand-binding site and is inserted between β-sheets 2 and 3 in the β-propeller (Xiong et al 2001(Xiong et al , 2004.…”

“…The β-subunit also contains a βI domain that is homologous to the inserted αI domain found in the α-subunits. This highly conserved region of about 240 residues also contains two additional sections that either play a role in ligand binding-the specificitydetermining loop-or in forming a critical interface with the β-propeller of the α-subunit (Huang et al 2000;Xiong et al 2001). The βI domain also contains a MIDAS site similar to the αI domain, and this site is important in mediating ligand binding to negatively charged amino acid residues.…”

“…In addition to the MIDAS site, the βI domain contains two other metal ion-binding sites called the adjacent metal ion-dependent adhesion site (ADMIDAS) and the synergistic metal ion-binding site (SyMBS) (Xiao et al 2004). The βI domain functions to either bind ligands directly in integrins lacking the inserted αI domain or to regulate the binding activity of α-subunits containing the αI domain (Xiong et al 2001;Xiao et al 2004).…”

“…extended with a closed headpiece (high affinity); (3) ligand occupied, i.e. extended with an open headpiece (Xiong et al 2001(Xiong et al , 2002Shimaoka et al 2003;Xiao et al 2004). At the present time, two models are proposed to describe the process of integrin activation: the 'deadbolt' model and the 'switchblade' model (Xiong et al 2003;Luo et al 2007).…”