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Polar mutations in membrane proteins as a biophysical basis for disease
Author(s) -
Partridge Anthony W.,
Therien Alex G.,
Deber Charles M.
Publication year - 2002
Publication title -
peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.10313
Subject(s) - chemistry , mutant , side chain , polar , mutation , lipid bilayer , transmembrane protein , biophysics , transmembrane domain , membrane protein , bilayer , steric effects , protein structure , molecular dynamics , stereochemistry , biochemistry , membrane , gene , computational chemistry , biology , organic chemistry , physics , receptor , astronomy , polymer
Transmembrane (TM) α‐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. © 2002 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 66: 350–358, 2002