Polar zippers: Their role in human disease


  • Max Perutz

    Corresponding author
    1. MRC Laboratory of Molecular Biology, Cambridge CB2 2QH, United Kingdom
    • MRC Laboratory of Molecular Biology, Cambridge CB2 2QH, UK
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Ascaris hemoglobin consists of 8 subunits, each of which contains a C-terminal peptide with the sequence Glu-Glu-Lys-His repeated 4 times. When plotted on a β-strand, this sequence leads to alternate lysines and glutamates on one side of the strand, and alternate glutamates and histidines on the other side, suggestive of a polar zipper that links the subunits together. A computer search of the protein database showed that the same or similar sequences also occur in other proteins. Some contain long repeats of Asp-Arg or Glu-Arg, among them the small nuclear ribonucleo-U1 70K protein, which is an autoantigen in systemic lupus erythematosis. These repeats appear to constitute the dominant epitopes in the autoimmune reaction. Single chains with Asp-Arg repeats may form α-helices in which alternate positively charged ridges and negatively charged grooves compensate each other. Several separate chains with Asp-Arg repeats could compensate each other's charges optimally by zipping together to β-sheets.

Several homeodomains of Drosophila, as well as the human transcription factor SP1, contain repeats of glutamines. Molecular modeling, circular dichroism, and electron and X-ray diffraction studies of a synthetic poly(L-glutamine) showed that it forms β-sheets held together by hydrogen bonds between the main-chain and side-chain amides. Published data suggest that the function of these glutamine repeats consists of joining essential transcription factors bound to distant segments of DNA.

The study of the structure and function of glutamine repeats has assumed medical importance with the discovery that Huntington's disease and 3 other dominantly inherited diseases are associated with a lengthening of glutamine repeats in the proteins coded for by the affected genes.