Polar zippers: their role in human disease.
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 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 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 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 modeling, circular dichroism, and 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 of joining essential transcription factors bound to distant segments of DNA.(ABSTRACT TRUNCATED AT 250 WORDS)
Perutz
M
M
MRC Laboratory of Molecular Biology, Cambridge, United Kingdom.
D000595:Amino Acid Sequence; D000818:Animals; D001200:Ascaris / Q000737:chemistry; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D005973:Glutamine; D006454:Hemoglobins / Q000737:chemistry; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology; D008969:Molecular Sequence Data; D009422:Nervous System Diseases / Q000235:genetics; D012091:Repetitive Sequences, Nucleic Acid; D017411:Ribonucleoproteins, Small Nuclear / Q000737:chemistry / Q000276:immunology
D006454:Hemoglobins; D017411:Ribonucleoproteins, Small Nuclear; D005973:Glutamine