Hinges, swivels and switches: the role of prolines in signalling via transmembrane alpha-helices

Extracellular signals are transduced across membranes via conformational ch anges in the transmembrane domains (TMs) of ion channels and G-protein-coup led receptors (GPCRs). Experimental and simulation studies indicate that su ch conformational switches in transmembrane alpha -helices can be generated by proline-containing motifs that form molecular hinges. Computational app roaches tested on model channel-forming peptides (e.g. alamethicin) reveal functional mechanisms in gap-junction proteins (such as connexin) and volta ge-gated K+ channels. Similarly, functionally important roles for proline-b ased switches in TM6 and TM7 were identified in GPCRs. However, hinges in t ransmembrane helices are not confined to proline-containing sequence motifs , as evidenced by a non-proline hinge in the M2 helix of the nicotinic acet ylcholine receptor. This helix lines the pore and plays a key role in the g ating of this channel.