The 3D structures of the aquaporin and glycerol facilitator family members do not seem related to 7TMRs at first glance,14 but the particular arrangement of a-helices means that they should not be ignored. These water and substrate channel proteins consist of 6TM helices and two half-TM helices that are apposed amino-terminally in the 3D structure to produce a seventh helical TM span (like an extended arrangement of the antibiotic half-helix dimer, gramicidin A, 1jno). The final topography of 2.5:3.5:1 helices, in order along the primary sequence, is very reminiscent of a 7TMR (Figure 10.3). The conformations of the two half-TM helices determine that both the amino and carboxyl termini of the channel protein are on the same (cyto-plasmic) side of the plasma membrane.

Domain swapping of the helices or incorporation of the periplasmic helical extensions can easily generate a multispanning protein with the amino and carboxyl termini on opposite sides of the bilayer, just like a 7TMR. Such contorted membrane orientations should not exclude the aquaporin-like structures from consideration as 7TMR models, as the recently discovered adiponectin Q subfamily has shown. This unusual subfamily consists of two major receptors for adiponectin, a 30-kDa ligand that forms higher order bioactive complexes, and three subtypes of membrane progestin receptors that bind a small hydrophobic steroid. From accessibility studies,15 it appears that adiponectin 7TMRs lie upside-down in the lipid bilayer, in a manner similar to molecule @ in Figure 10.3B. The many demonstrations of dimeric 7TMRs may need embellishing with the possibility that the two receptors may associate in the antiparallel manner observed in the crystal structure of rhodopsin, with one up and one down or in the exclusively upside-down orientation of the adiponectin (and presumably progestin) receptors.

Thus, there are many ways to produce a 7TMR structure and these three disparate examples will, hopefully, fire the imagination and allow many novel scenarios to be envisaged — and tested.

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