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G-protein coupled receptor Folding and Misfolding
110-187 disulfide bond
110-187 disulfide bond is missing in cannabinoid receptors, ref. Onaivi, E.S., C.M. Leonard, H. Ishiguro, P.W. Zhang, Z. Lin, B.E. Akinshola, and G.R. Uhl, Endocannabinoids and cannabinoid receptor genetics. Prog Neurobiol, 2002. 66(5): p. 307-44 (otherwise this review is mostly on genetics)
Rescue of misfolded receptors
concept of "pharmacological chaperones": Morello, J.P., U.E. Petaja-Repo, D.G. Bichet, and M. Bouvier, Pharmacological chaperones: a new twist on receptor folding. Trends Pharmacol Sci, 2000. 21(12): p. 466-9:
- ligands with pharmacological selectivity can rescue targeting and function of misfolded proteins
- examples for such ligands:
cystic fibrosis cystic fibrosis TM conductance regulator (CFTR) glycerol, dimethylsulfoxide (DMSO), trimethylamine-N-oxide (TMAO)
emphysema and liver disease alpha1-antitrypsin glycerol
nephrogenic diabetes insipidus aquaporin-2 glycerol, DMSO, TMAO
nephrogenic diabetes insipidus Vasopressin V2 receptor SR121463A, VPA985
Retinitis pigmentosa rhodopsin 11-cis retinal
Fabry alpha-galactosidase A 1-deoxy-galactonojirimycin
Cancer p53 CP31398, CP257042
none P-glycoprotein capsaicin, cyclosporin, vinblastin, verapamil
- best example for misfolding disease is cystic fibrosis: Delta F508 mutation in CFTR is a trafficking mutation that blocks maturation of the protein in the ER and targets it for premature proteolysis. If the mutant protein is redirected to the cell surface, a healthy cell is restored.
- low temperature or chemical agents such as glycerol, DMSO, TMAO slow down the misfolding and/or degradation processes, so that correctly folded CFTR can escape to the cell surface
- for V2 receptor and for rhodopsin, ligand can increase the proportion of folded protein (rhodopsin is not mentioned in the Morello et al paper, but is also a good example)