title: Two serine residues distinctly regulate the rescue function of Humanin, an inhibiting factor of Alzheimer's disease-related neurotoxicity: functional potentiation by isomerization and dimerization.
abstract: The 24-residue peptide Humanin (HN), containing two Ser residues at positions 7 and 14, protects neuronal cells from insults of various Alzheimer's disease (AD) genes and A beta. It was not known why the rescue function of (S14G)HN is more potent than HN by two to three orders of magnitude. Investigating the possibility that the post-translational modification of Ser14 might play a role, we found that HN with D-Ser at position 14 exerts neuroprotection more potently than HN by two to three orders of magnitude, whereas D-Ser7 substitution does not affect the rescue function of HN. On the other hand, S7A substitution nullified the HN function. Multiple series of experiments indicated that Ser7 is necessary for self-dimerization of HN, which is essential for neuroprotection by this factor. These findings indicate that the rescue function of HN is quantitatively modulated by d-isomerization of Ser14 and Ser7-relevant dimerization, allowing for the construction of a very potent HN derivative that was fully neuroprotective at 10 pM against 25 microM A beta1-43. This study provides important clues to the understanding of the neuroprotective mechanism of HN, as well as to the development of novel AD therapeutics.
authors.affiliation: Department of Pharmacology, KEIO University School of Medicine, Medical Research Center, Tokyo, Japan.
authors.forename: Kenzo
authors.initials: K
authors.lastname: Terashita
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hashimoto
authors.forename: Takako
authors.initials: T
authors.lastname: Niikura
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Tajima
authors.forename: Yohichi
authors.initials: Y
authors.lastname: Yamagishi
authors.forename: Miho
authors.initials: M
authors.lastname: Ishizaka
authors.forename: Masaoki
authors.initials: M
authors.lastname: Kawasumi
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Chiba
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Kanekura
authors.forename: Marina
authors.initials: M
authors.lastname: Yamada
authors.forename: Mikiro
authors.initials: M
authors.lastname: Nawa
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Kita
authors.forename: Sadakazu
authors.initials: S
authors.lastname: Aiso
authors.forename: Ikuo
authors.initials: I
authors.lastname: Nishimoto
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism*; D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000633:toxicity; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis / Q000235:genetics / Q000633:toxicity; D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006822:Hybrid Cells; D047908:Intracellular Signaling Peptides and Proteins; D007536:Isomerism; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism* / Q000494:pharmacology; D010766:Phosphorylation; D011506:Proteins / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D012694:Serine / Q000235:genetics; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D047908:Intracellular Signaling Peptides and Proteins; D018696:Neuroprotective Agents; D011506:Proteins; D011993:Recombinant Fusion Proteins; C427211:humanin; D012694:Serine