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- Title
Humanin antagonists: mutants that interfere with dimerization inhibit neuroprotection by Humanin.
- Authors
Hashimoto, Yuichi; Terashita, Kenzo; Niikura, Takako; Yamagishi, Yohichi; Ishizaka, Miho; Kanekura, Kohsuke; Chiba, Tomohiro; Yamada, Marina; Kita, Yoshiko; Aiso, Sadakazu; Matsuoka, Masaaki; Nishimoto, Ikuo
- Abstract
The 24-residue peptide Humanin (HN) protects neuronal cells from insults of various Alzheimer's disease (AD) genes and Aβ by forming a homodimer. We have previously shown that P3A, S7A, C8A, L9A, L12A, T13A, S14A and P19A mutations nullify the neuroprotective function of HN [Yamagishi, Y., Hashimoto, Y., Niikura, T. & Nishimoto, I. (2003) Peptides, 24, 585-595]. Here we examined whether any of these 'null' mutants could function as dominant-negative mutants. Homodimerization-defective mutants, P3A-, L12A-, S14A- and P19A-HN, specifically blocked neuroprotection by HN, but not by activity-dependent neurotrophic factor. Furthermore, insertion of S7A, the mutation that blocks the homodimerization of HN, but not insertion of GSA abolished the antagonizing function of L12A-HN. While L12A-HN and G5A/L12A-HN actually inhibited HN homodimerization, S7A/L12A-HN had no effect. These data indicate that P3A-, L12A-, Si 4A- and P19A-HN function as HN antagonists by forming an inactive dimer with HN. This study provides a novel insight into the understanding of the in vivo function of HN, as well as into the development of clinically applicable HN neutralizers.
- Subjects
NEURONS; ALZHEIMER'S disease; GENES; GENETIC mutation; DIMERS; GENETICS
- Publication
European Journal of Neuroscience, 2004, Vol 19, Issue 9, p2356
- ISSN
0953-816X
- Publication type
Article
- DOI
10.1111/j.0953-816X.2004.03298.x