Abstract
Integrins are heterodimeric (αβ) cell surface receptors that are potential therapeutic targets for a number of diseases. Despite the existence of structural data for all parts of integrins, the structure of the complete integrin receptor is still not available. We have used available structural data to construct a model of the complete integrin receptor in complex with talin F2–F3 domain. It has been shown that the interactions of integrins with their lipid environment are crucial for their function but details of the integrin/lipid interactions remain elusive. In this study an integrin/talin complex was inserted in biologically relevant bilayers that resemble the cell plasma membrane containing zwitterionic and charged phospholipids, cholesterol and sphingolipids to study the dynamics of the integrin receptor and its effect on bilayer structure and dynamics. The results of this study demonstrate the dynamic nature of the integrin receptor and suggest that the presence of the integrin receptor alters the lipid organization between the two leaflets of the bilayer. In particular, our results suggest elevated density of cholesterol and of phosphatidylserine lipids around the integrin/talin complex and a slowing down of lipids in an annulus of ~30 Å around the protein due to interactions between the lipids and the integrin/talin F2–F3 complex. This may in part regulate the interactions of integrins with other related proteins or integrin clustering thus facilitating signal transduction across cell membranes.
Highlights
Integrins are heterodimeric cell surface receptors that are potential therapeutic targets for a number of diseases
In this study an integrin/talin complex was inserted in biologically relevant bilayers that resemble the cell plasma membrane containing zwitterionic and charged phospholipids, cholesterol and sphingolipids to study the dynamics of the integrin receptor and its effect on bilayer structure and dynamics
In the tal_ab systems (Table 2) the ectodomain (3IJE in Fig. 1) was removed, in order to enable us to examine the intrinsic dynamics of the talin F2–F3/ab TM complex (3G9W/2K9J in Fig. 1) and of its interactions with the bilayer in the absence of possible modulation by the ectodomain
Summary
Integrins are heterodimeric (ab) cell surface receptors that are potential therapeutic targets for a number of diseases. Binding of the head domain of the cytosolic protein talin to the cytoplasmic regions of the b integrin (Anthis et al 2009; Calderwood 2004; Kalli et al 2013a) has been shown to result in reorientation of the integrin TM helices (Kalli et al 2011a). This in turn may result to substantial conformational changes in the integrin ectodomain resulting in integrin inside-out activation (Shattil et al 2010). The F2 and F3 subdomains have positively charged patches (or loops) which interact with the lipids of the intracellular leaflet of the cell membrane (Anthis et al 2009; Elliott et al 2010), and these interactions are suggested to be important for integrin activation (Anthis et al 2009; Elliott et al 2010; Kalli et al 2010, 2011a)
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