Intramembrane helix-helix association in oligomerization and transmembrane signaling.
In spite of our greatly expanded knowledge of the primary structures of transbilayer receptor proteins, our knowledge of the tertiary and quaternary structures that define the biological activity of these receptors is scant. If we assume that the transmembrane regions of receptor proteins form stable alpha-helices regardless of the mechanism of insertion, a two-stage model of protein folding can be applied. For a multiple-helix protein, the two-stage model would predict that stable helical formation would be followed by an association of the helices to form the appropriate tertiary/quaternary structure. The two-stage model of protein folding is supported by various experiments with bacteriorhodopsin demonstrating that separate proteolytic fragments of bacteriorhodopsin can be refolded separately and can specifically recognize each other in order to associate and form a biologically active molecule. At the level of the bilayer, we propose that the energetics required for the association and packing of the helical transmembrane regions of a multiple-helix protein should not be significantly different from the association of separate single-helix proteins into an oligomer. Given the homogeneity in primary and secondary structure of the transmembrane regions of single-helix proteins, the association of multiple monomers may physically define high vs low affinity states and be a plausible mechanism of signal transduction. Increasing data suggest that oligomerization of receptor proteins may be involved in signal transduction. The transmembrane domains of receptor proteins appear to contain information critical to signaling and may be involved in a close contact site between receptors. This observation allows the two-stage model of protein folding for multiple-helix proteins to be directly applied to the oligomerization of single-helix receptor proteins. In addition, significant data suggest that the ectodomains and cytoplasmic domains are also involved in signaling and oligomerization of receptor molecules. In effect, the present data suggest that the most plausible model, both mechanistically and energetically, is one that includes both oligomerization and a global allosteric conformational change involving all of the defined domains of the receptor molecule. An oligomerization/conformational change model would predict that new sites of close contact would occur between the domains of the receptor molecule, some of which may be between the transmembrane helices. Therefore, experimenters should be able to generate peptides or small molecules that can specifically interfere with either the oligomerization or generation of new close-contact sites involved in the conformational change of the receptor that leads to signaling.(ABSTRACT TRUNCATED AT 400 WORDS)
Bormann
B J
BJ
Department of Immunology, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut 06877.
Engelman
D M
DM
D000818:Animals; D008051:Lipid Bilayers; D046911:Macromolecular Substances; D008563:Membrane Lipids / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism*; D008961:Models, Structural; D011487:Protein Conformation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction
D008051:Lipid Bilayers; D046911:Macromolecular Substances; D008563:Membrane Lipids; D008565:Membrane Proteins; D011956:Receptors, Cell Surface; D011505:Protein-Tyrosine Kinases