Structure of the Integrin β3 Transmembrane Segment in Phospholipid Bicelles and Detergent Micelles

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Abstract

Integrin adhesion receptors transduce bidirectional signals across the plasma membrane, with the integrin transmembrane domains acting as conduits in this process. Here, we report the first high-resolution structure of an integrin transmembrane domain. To assess the influence of the membrane model system, structure determinations of the β3 integrin transmembrane segment and flanking sequences were carried out in both phospholipid bicelles and detergent micelles. In bicelles, a 30-residue linear α-helix, encompassing residues I693−H772, is adopted, of which I693-I721 appear embedded in the hydrophobic bicelle core. This relatively long transmembrane helix implies a pronounced helix tilt within a typical lipid bilayer, which facilitates the snorkeling of K716’s charged side chain out of the lipid core while simultaneously immersing hydrophobic L717−I721 in the membrane. A shortening of bicelle lipid hydrocarbon tails does not lead to the transfer of L717−I721 into the aqueous phase, suggesting that the reported embedding represents the preferred β3 state. The nature of the lipid headgroup affected only the intracellular part of the transmembrane helix, indicating that an asymmetric lipid distribution is not required for studying the β3 transmembrane segment. In the micelle, residues L717−I721 are also embedded but deviate from linear α-helical conformation in contrast to I693−K716, which closely resemble the bicelle structure.

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