Polar zippers: their role in human disease

Ascaris hemoglobin consists of eight subunits, each of which contains a C-terminal peptide with the sequence Glu-Glu-Lys-His repeated four times. When plotted on a beta-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 which 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 alpha-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 beta-sheets. Several homeodomains of Drosophila as well as the human transcription factor SP1 contain repeats of glutamines. Molecular modelling, circular dichroism, electron and X-ray diffraction studies of a synthetic poly(L-glutamine) showed that it forms beta-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 in 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 four other dominantly inherited diseases are associated with a lengthening of glutamine repeats in the proteins coded for by the affected genes.