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

Trends Pharmacol Sci. 2000 Nov;21(11):445-51. doi: 10.1016/s0165-6147(00)01553-4.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / chemistry
  • ATP Binding Cassette Transporter, Subfamily B / physiology
  • Amino Acid Sequence
  • Animals
  • Connexins / chemistry
  • Connexins / physiology
  • Humans
  • Ion Channels / chemistry
  • Ion Channels / physiology
  • Membrane Proteins / chemistry*
  • Membrane Proteins / pharmacology*
  • Molecular Sequence Data
  • Proline / chemistry*
  • Proline / physiology*
  • Protein Conformation
  • Protein Structure, Secondary
  • Receptors, Cell Surface / chemistry
  • Receptors, Cell Surface / physiology
  • Signal Transduction / physiology*


  • ATP Binding Cassette Transporter, Subfamily B
  • Connexins
  • Ion Channels
  • Membrane Proteins
  • Receptors, Cell Surface
  • Proline