Partridge Anthony W, Therien Alex G, Deber Charles M
Division of Structural Biology & Biochemistry, Research Institute, Hospital for Sick Children, Toronto M5G 1X8, Ontario, Canada.
Biopolymers. 2002;66(5):350-8. doi: 10.1002/bip.10313.
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.
跨膜（TM）α螺旋被脂质双层的烃链所包围。这种环境的低介电常数使得具有极性侧链的残基以非氢键结合状态存在极为不利。因此，在与野生型极性残基伙伴结合时，极性TM突变体在某些情况下可能会产生非天然氢键，这可能会损害天然蛋白质的结构/功能，并可能导致疾病状态。我们研究了蛋白质突变数据库，发现了许多基于TM的非极性到极性突变的例子，这些突变实际上是人类疾病的一个原因。在这里，我们回顾了此类突变可能产生的各种分子缺陷，包括通过侧链-侧链螺旋间氢键交联阻碍蛋白质动力学；通过空间位阻改变螺旋堆积；以及破坏蛋白质活性位点。我们进一步指出，相反的情况——膜嵌入的极性到非极性突变——同样可能导致人类疾病，这意味着天然螺旋间氢键在稳定天然TM结构域中也可能起关键作用。作为一个具体例子，我们表明，与在可溶性结构域中相比，甘氨酸到精氨酸的突变在TM结构域中发生的统计频率更高，这表明基于TM的G-to-R突变具有很高的疾病“表型倾向”。更全面地了解蛋白质TM结构域中涉及极性残基的突变如何转化为功能受损，可能有助于开发新的治疗方法。
