The integrins are a family of proteins that reside in the plasma membrane of most cells of multicellular organisms

[1]. They are the primary receptors that recognize the protein components of the extracellular matrix (ECM). Binding to the ECM triggers intracellular signaling pathways that regulate adhesion, migration, growth, and survival

[2]. These pathways often intersect with those generated by receptors for soluble factors [3]. However, integrins differ from "classical" signaling receptors in a number of ways. First, because the ECM is static and polyvalent, integrins cluster at the sites of attachment. Second, ligand-bound integrins form connections with the cytoskeleton that regulate cell shape and rigidity, as well as providing platforms for signaling complexes. Third, integrins can also transmit signals from the inside of the cell to the outside. Thus, integrin signaling is a bidirectional process that evolves rapidly in time and space as the cell adapts to its environment, allowing integrins to be sensors and messengers of the surroundings and shape of the cell, as well as the mechanical forces acting upon it [2].

Integrin signaling typically involves conformational changes within the integrin molecule that are propagated across the plasma membrane. Under some circumstances, lateral self-association of integrins ("clustering") is sufficient for signaling [4,5], and a number of molecules that associate laterally with integrins have also been identified that contribute to signaling [6]. However, the focus of this section is on the conformational changes within individual molecules that control the recognition of extracellular and intracellular binding partners.


Integrins are ap heterodimers, consisting of a head domain from which emerge two legs, one from each subunit, ending in a pair of single-pass transmembrane helices and short cytoplasmic tails (Fig. 1). In the absence of ligand, bonds between the legs and tails are believed to hold the head in an inactive or resting conformation that has low affinity for ligand [7,8]. During outside-in signaling, ECM binding to the head triggers conformational changes that are propagated down the legs and through the plasma membrane, leading to a reorganization of the C-terminal tails that allows them to bind intracellular proteins [3]. During inside-out signaling, cytosolic proteins bind and sequester one or both of the cytoplasmic tails, triggering conformational changes in the head that lead to a high-affinity active integrin.

The integrin "head" is composed of a seven-bladed propeller from the a-subunit that makes an intimate contact with a GTP-ase-like domain of the p-subunit (called either an A or I domain by different authors, and I domain here), in a manner that strongly resembles the heterotrimeric G proteins [9]. Instead of a catalytic center, the I domain contains an invariant ligand binding site called MIDAS (metal ion-dependent adhesion site), in which a metal ion is coordinated by three loops from the I domain, and a glu-tamic or aspartic acid from the ligand completes an octahedral coordination sphere around the metal. Specificity is provided by ligand contacts to the surface surrounding the MIDAS, which is highly variable among integrin family members, and in some cases by additional contact to the a-subunit propeller. A helix that emanates from one of the MIDAS loops packs against the central axis of the propeller,

Figure 1 Integrin domain organization. Activation epitopes [13,33] are shown as red, blue, and cyan disks.

thus providing a potential link between ligand binding and the quaternary structure. In certain integrins, an additional I domain (a-I) is inserted into the a-subunit, between two loops on the upper surface of the propeller, where it forms the major ligand binding site. Modeling studies indicate that this domain will form contacts with both the propeller and the P-I domain that regulate the conformation and ligand affinity of the domain, and indeed mutations to the outer surface of the domain can lead to loss- or gain-of-function [10]. The remaining domains of the two subunits form a pair of legs that contact each other along their length, ending at their closely apposed C termini. The legs are followed by a pair of single-pass transmembrane helices and short (except for P4) cytoplasmic tails, typically 20 to 50 residues in length. These tails lack catalytic activity and transduce signals by binding to intracellular structural and signaling proteins.

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