The Transmembrane Structure of Integrin αIIbβ3: Significance for Signal Transduction

The formation of multicellular organisms requires concerted action by cells, which alter their adhesive and migratory behaviors. Cell adhesion and migration are tightly regulated by intraand extracellular signals, which are conveyed through the cellular membrane by specialized receptors known as integrins. Integrins are the starting point of a variety of signaling cascades and are involved in a multitude of physiological events important to multicellular organism morphogenesis, ranging from cell adhesion to migration, apoptosis, and angiogenesis as well as pathophysiological behaviors such as those found in cancer metastasis. The transmembrane (TM) domains of integrins are at the center of integrin signaling. Recently, a structure of the TM domains of the aIIbb3 integrin has been reported that sheds light on the signal transduction mechanism of integrins. Integrins are essential TM proteins that couple the extracellular matrix to the cytoskeleton. They consist of noncovalently bound heterodimers, in which each subunit (a and b) contains one TM helix. With eighteen a and eight b subunit types identified, there are 24 known distinct heterodimer combinations with partially overlapping yet specific function. Cells regulate their integrin-mediated adhesion through a variety of mechanisms on different time scales. On the slower time scale, expression patterns are altered by external signals, such as growth factors. On faster time scales, integrins can be redistributed (by clustering or recycling) on the cellular surface, change their intracellular attachment state to the cytoskeleton as exemplified by different lateral mobilities of integrins on a single cell, or alter the affinity state for their extracellular ligand (integrin activation). Changes in the affinity state are correlated with integrin conformational changes, which act as one potential mechanism to relay signals either from the extracellular to the intracellular space (outside-in signaling) or vice versa (inside-out signaling). Integrins are bidirectional signaling molecules, as both signaling directions take place along an allosteric pathway. The two TM helices of the integrin heterodimer are pivotal in signaling events as linkers between the extracellular and intracellular domains. Hence, a variety of groups have pursued different strategies to understand the role of the TM domains in signaling. It was postulated that the TM helices were not merely connectors between the extraand the intracellular space but active structures forming specific heterodimers. However, the structural details of this TM heterodimer have remained elusive until recently. In their recent report, Lau et al. have solved the structure of the aIIbb3 integrin heterodimer in its resting state using highly sophisticated, well-designed NMR spectroscopy experiments on the TM domains in bicelles. This experimentally determined structure allows a solid, structural basis for the prior experimental biochemical results by providing a foundation for an atomistic understanding of TM integrin signaling. The experimental structure shows a right-handed helical dimer (Figure 1). Given that the majority of soluble helix dimers form left-handed structures, this unusual right-