Integrin structure, activation, and interactions

Abstract

Integrins are large, membrane-spanning, heterodimeric proteins that are essential for a metazoan existence. All members of the integrin family adopt a shape that resembles a large "head" on two "legs," with the head containing the sites for ligand binding and subunit association. Most of the receptor dimer is extracellular, but both subunits traverse the plasma membrane and terminate in short cytoplasmic domains. These domains initiate the assembly of large signaling complexes and thereby bridge the extracellular matrix to the intracellular cytoskeleton. To allow cells to sample and respond to a dynamic pericellular environment, integrins have evolved a highly responsive receptor activation mechanism that is regulated primarily by changes in tertiary and quaternary structure. This review summarizes recent progress in the structural and molecular functional studies of this important class of adhesion receptor.

Figure 1.

Integrin structure. (A) Domain structure of αxβ2 (Xie et al. 2009); (B) structure of αxβ2 using same color code as A (drawn with PyMOL [DeLano Scientific] using PDB coordinates 3K6S); (C) cartoon representation of bent and upright conformations showing approximate dimensions.

Figure 2.

An illustration of the movement of α7 helix in the I domains and the swing-out of the hybrid domain (the domains are defined in Fig. 1). The top pair corresponds to the closed and open conformations of an integrin without an inserted α-I domain whereas the lower pair represents the situation when there is an α-I domain present. The intrinsic ligand is a glutamate (E310 in αL).

Figure 3.

Three β-I domain metal-binding sites in αXβ2 (Zhu et al. 2008); aspartate ligands to the metal ions are shown in cyan (from PDB:3FCS); figure drawn using PyMOL (DeLano Scientific).

Figure 4.

(A) NMR structure of the complex between the αIIb (blue) and β3 (red) TM domains (PDB: 2K9J). The approximate position of the membrane glycerol backbone is shown by gray lines. (B) The talin F2 (blue)/F3 (yellow) domain pair in complex with a β integrin tail (red). The salt bridge that forms between K324 on F3 and D723 in the tail is shown; some key Lys and Arg residues are indicated in blue near the putative membrane interface with the F2 domain. B was constructed from a composite of coordinates of the talin/β complex (PDB: 3G9W; [Anthis et al. 2009]) and the membrane complex (PDB:2K9J [Lau et al. 2009]). Images made using PyMOL (DeLano Scientific).