John E. Baenziger and colleagues have suggested that lipids regulate the function of the nAChR
by affecting the interaction of helix M4, which lies at the protein/lipid interface (Fig. 1.30) with the rest
of the TM region: in the absence of specific lipids (cholesterol and acidic lipids), M4 would move in
such a way that conformational changes in the extracellular region would become uncoupled from
those in the TM one (daCosta and Baenziger 2009, 2013; Baenziger et al. 2015; Hénault et al. 2015)
(Fig. 1.33). This point will be further addressed when comparing the effects of detergents and APols on
the allosteric transitions of the nAChR (Chap. 5, §§ 5.4 and 5.6).
Fig. 1.32 Conformational changes thought to underlie the desensitization of pLGICs. The cartoon
illustrates the relative positions of the extracellular domains (ECD) and transmembrane domains (TMD)
in the α4β2 acetylcholine receptor (desensitized) compared to the open conformation of the glycine
receptor (GlyR) and the partially desensitized conformation of the GABA A receptor (From MoralesPerez et al. 2016. # 2013 Macmillan Publishers Limited, part of Springer Nature. All rights reserved).
Fig. 1.33 Decoupling of the nAChR in the absence of functionally critical lipids, cholesterol and
phosphatidic acid (PA). (A) The nAChR from native Torpedo membranes undergoes agonist-induced
conformational transitions from resting (R) to open (O) and then desensitized (D) conformations. The
nAChR in reconstituted membranes also adopts an uncoupled conformation (U) that binds agonist but
typically does not undergo the transition to the open or desensitized states. (B) Schematic diagram showing
the current model of lipid-dependent uncoupling, illustrated using a single nAChR subunit. The lipidexposed M4 TM helix likely plays a key role in sensing the lipid bilayer. In unfavorable membrane
environments, the conformation of M4 may change, thus weakening interactions between the β1-β2 (light
blue)/β6-β7 (green) loops of the extramembrane region and the M2–M3 linker (red) of the TM region (for
details, see daCosta and Baenziger 2009) (From daCosta and Baenziger 2013. # 2013 Macmillan
Publishers Limited, Nature. All rights reserved).
1.6 Dynamics of Transmembrane Regions and the Function of Membrane Proteins
43
by affecting the interaction of helix M4, which lies at the protein/lipid interface (Fig. 1.30) with the rest
of the TM region: in the absence of specific lipids (cholesterol and acidic lipids), M4 would move in
such a way that conformational changes in the extracellular region would become uncoupled from
those in the TM one (daCosta and Baenziger 2009, 2013; Baenziger et al. 2015; Hénault et al. 2015)
(Fig. 1.33). This point will be further addressed when comparing the effects of detergents and APols on
the allosteric transitions of the nAChR (Chap. 5, §§ 5.4 and 5.6).
Fig. 1.32 Conformational changes thought to underlie the desensitization of pLGICs. The cartoon
illustrates the relative positions of the extracellular domains (ECD) and transmembrane domains (TMD)
in the α4β2 acetylcholine receptor (desensitized) compared to the open conformation of the glycine
receptor (GlyR) and the partially desensitized conformation of the GABA A receptor (From MoralesPerez et al. 2016. # 2013 Macmillan Publishers Limited, part of Springer Nature. All rights reserved).
Fig. 1.33 Decoupling of the nAChR in the absence of functionally critical lipids, cholesterol and
phosphatidic acid (PA). (A) The nAChR from native Torpedo membranes undergoes agonist-induced
conformational transitions from resting (R) to open (O) and then desensitized (D) conformations. The
nAChR in reconstituted membranes also adopts an uncoupled conformation (U) that binds agonist but
typically does not undergo the transition to the open or desensitized states. (B) Schematic diagram showing
the current model of lipid-dependent uncoupling, illustrated using a single nAChR subunit. The lipidexposed M4 TM helix likely plays a key role in sensing the lipid bilayer. In unfavorable membrane
environments, the conformation of M4 may change, thus weakening interactions between the β1-β2 (light
blue)/β6-β7 (green) loops of the extramembrane region and the M2–M3 linker (red) of the TM region (for
details, see daCosta and Baenziger 2009) (From daCosta and Baenziger 2013. # 2013 Macmillan
Publishers Limited, Nature. All rights reserved).
1.6 Dynamics of Transmembrane Regions and the Function of Membrane Proteins
43