title: Polar mutations in membrane proteins as a biophysical basis for disease.
abstract: Transmembrane (TM) alpha-helices are surrounded by the hydrocarbon chains of the lipid bilayer. The low dielectric constant of this environment makes it extremely unfavorable for a residue with a polar side chain to exist in a non-H-bonded state. Therefore, in combination with a wild-type polar residue partner, a polar TM mutant could generate, in some cases, a non-native H-bond that could impair native protein structure/function-and possibly lead to a disease state. We have examined protein mutation databases and have found many examples of TM-based apolar to polar mutations that are, in fact, a cause of human disease. Here we review the various molecular defects that such mutations can produce, including impeding protein dynamics by side-chain-side-chain interhelical H-bond cross-links; alteration of helical packing through steric hindrance; and disruption of a protein active site. We further note that the reverse case--membrane-embedded polar to apolar mutations--can similarly cause human disease, implying that native interhelical H-bonds can also play pivotal roles in stabilizing native TM domains. As a specific example, we show that the Gly to Arg mutation occurs statistically more frequently in TM domains as compared to its occurrence in soluble domains, suggesting that TM-based G-to-R mutations have a high "phenotypic propensity" for disease. A more complete understanding of how mutations involving polar residues in TM domains of proteins translate into compromised function may aid in the development of novel therapeutics.
authors.affiliation: Division of Structural Biology & Biochemistry, Research Institute, Hospital for Sick Children, Toronto M5G 1X8, Ontario, Canada.
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Partridge
authors.forename: Alex G
authors.initials: AG
authors.lastname: Therien
authors.forename: Charles M
authors.initials: CM
authors.lastname: Deber
mesh_terms: D000495:Allosteric Site; D001665:Binding Sites; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D006801:Humans; D006860:Hydrogen Bonding; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics*; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010641:Phenotype; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry
chemical_list: D008565:Membrane Proteins; D011994:Recombinant Proteins