Hinges, swivels and switches: the role of prolines in signalling via transmembrane alpha-helices.
Extracellular signals are transduced across membranes via conformational changes in the transmembrane domains (TMs) of ion channels and G-protein-coupled receptors (GPCRs). Experimental and simulation studies indicate that such conformational switches in transmembrane (alpha-helices can be generated by proline-containing motifs that form molecular hinges. Computational approaches tested on model channel-forming peptides (e.g. alamethicin) reveal functional mechanisms in gap-junction proteins (such as connexin) and voltage-gated K+ channels. Similarly, functionally important roles for proline-based switches in TM6 and TM7 were identified in GPCRs. However, hinges in transmembrane helices are not confined to proline-containing sequence motifs, as evidenced by a non-proline hinge in the M2 helix of the nicotinic acetylcholine receptor. This helix lines the pore and plays a key role in the gating of this channel.
Sansom
M S
MS
Department of Biochemistry, University of Oxford, UK. mark@biop.ox.ac.uk
Weinstein
H
H
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000737:chemistry / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D017630:Connexins / Q000737:chemistry / Q000502:physiology; D006801:Humans; D007473:Ion Channels / Q000737:chemistry / Q000502:physiology; D008565:Membrane Proteins / Q000737:chemistry* / Q000494:pharmacology*; D008969:Molecular Sequence Data; D011392:Proline / Q000737:chemistry* / Q000502:physiology*; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
D018435:ATP Binding Cassette Transporter, Subfamily B; D017630:Connexins; D007473:Ion Channels; D008565:Membrane Proteins; D011956:Receptors, Cell Surface; D011392:Proline