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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >KTKEGV repeat motifs are key mediators of normal alpha-synuclein tetramerization: Their mutation causes excess monomers and neurotoxicity
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KTKEGV repeat motifs are key mediators of normal alpha-synuclein tetramerization: Their mutation causes excess monomers and neurotoxicity

机译：KTKEGV repeat motifs are key mediators of normal alpha-synuclein tetramerization: Their mutation causes excess monomers and neurotoxicity

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摘要

alpha-Synuclein (alpha S) is a highly abundant neuronal protein that aggregates into beta-sheet-rich inclusions in Parkinson's disease (PD). aS was long thought to occur as a natively unfolded monomer, but recent work suggests it also occurs normally in alpha-helix-rich tetramers and related multimers. To elucidate the fundamental relationship between alpha S multimers and monomers in living neurons, we performed systematic mutagenesis to abolish self-interactions and learn which structural determinants underlie native multimerization. Unexpectedly, tetramers/multimers still formed in cells expressing each of 14 sequential 10-residue deletions across the 140-residue polypeptide. We postulated compensatory effects among the six highly conserved and one to three additional alpha S repeat motifs (consensus: KTKEGV), consistent with alpha S and its homologs beta- and gamma-synuclein all forming tetramers while sharing only the repeats. Upon inserting in-register missense mutations into six or more alpha S repeats, certain mutations abolished tetramer formation, shown by intact-cell cross-linking and independently by fluorescent-protein complementation. For example, altered repeat motifs KLKEGV, KTKKGV, KTKEIV, or KTKEGW did not support tetramerization, indicating the importance of charged or small residues. When we expressed numerous different in-register repeat mutants in human neural cells, all multimer-abolishing but no multimer-neutral mutants caused frank neurotoxicity akin to the proapoptotic protein Bax. The multimer-abolishing variants became enriched in buffer-insoluble cell fractions and formed round cytoplasmic inclusions in primary cortical neurons. We conclude that the alpha S repeat motifs mediate physiological tetramerization, and perturbing them causes PD-like neurotoxicity. Moreover, the mutants we describe are valuable tools for studying normal and pathological properties of alpha S and screening for tetramer-stabilizing therapeutics.

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