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Author Alsanousi, Nesreen ♦ Sugiki, Toshihiko ♦ Furuita, Kyoko ♦ So, Masatomo ♦ Lee, Young-Ho ♦ Fujiwara, Toshimichi ♦ Kojima, Chojiro
Source United States Department of Energy Office of Scientific and Technical Information
Content type Text
Language English
Subject Keyword APPLIED LIFE SCIENCES ♦ ALCOHOLS ♦ ANIMAL TISSUES ♦ BRAIN ♦ CONFORMATIONAL CHANGES ♦ ISOMERIZATION ♦ NUCLEAR MAGNETIC RESONANCE ♦ OXIDATION ♦ PEPTIDES ♦ RESIDUES ♦ SERINE ♦ STRUCTURE FUNCTIONS ♦ ZINC IONS
Abstract Humanin comprising 24 amino acid residues is a bioactive peptide that has been isolated from the brain tissue of patients with Alzheimer's disease. Humanin reportedly suppressed aging-related death of various cells due to amyloid fibrils and oxidative stress. There are reports that the cytoprotective activity of Humanin was remarkably enhanced by optical isomerization of the Ser14 residue from L to D form, but details of the molecular mechanism remained unclear. Here we demonstrated that Humanin D-Ser14 exhibited potent inhibitory activity against fibrillation of amyloid-β and remarkably higher binding affinity for amyloid-β than that of the Humanin wild-type and S14G mutant. In addition, we determined the solution structure of Humanin D-Ser14 by nuclear magnetic resonance (NMR) and showed that D-isomerization of the Ser14 residue enables drastic conformational rearrangement of Humanin. Furthermore, we identified an amyloid-β-binding site on Humanin D-Ser14 at atomic resolution by NMR. These biophysical and high-resolution structural analyses clearly revealed structure–function relationships of Humanin and explained the driving force of the drastic conformational change and molecular basis of the potent anti-amyloid-β fibrillation activity of Humanin caused by D-isomerization of the Ser14 residue. This is the first study to show correlations between the functional activity, tertiary structure, and partner recognition mode of Humanin and may lead to elucidation of the molecular mechanisms of the cytoprotective activity of Humanin. - Highlights: • Humanin D-Ser14 showed the strongest inhibitory activity against Aβ40 fibrillation. • NMR structure of Humanin D-Ser14 was determined in alcohol/water mixture solution. • Humanin D-Ser14 directly bound Aβ40 stronger than Humanin wild-type and Humanin S14G. • Aβ40 and zinc ion binding sites of Humanin D-Ser14 were identified. • Structure around Ser14 of Humanin is critical for Aβ40 binding and inhibitory activity.
ISSN 0006291X
Educational Use Research
Learning Resource Type Article
Publisher Date 2016-09-02
Publisher Place United States
Journal Biochemical and Biophysical Research Communications
Volume Number 477
Issue Number 4


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