title: Phosphorylation of Ser8 promotes zinc-induced dimerization of the amyloid-β metal-binding domain.
abstract: Zinc-induced aggregation of the amyloid-β peptide (Aβ) is a hallmark molecular feature of Alzheimer's disease (AD). Recently it was shown that phosphorylation of Aβ at Ser8 promotes the formation of toxic aggregates. In this work, we have studied the impact of Ser8 phosphorylation on the mode of zinc interaction with the Aβ metal-binding domain 1-16 using isothermal titration calorimetry, electrospray ionization mass spectrometry and NMR spectroscopy. We have discovered a novel zinc binding site ((6)HDpS(8)) in the phosphorylated peptide, in which the zinc ion is coordinated by the imidazole ring of His6, the phosphate group attached to Ser8 and a backbone carbonyl group of His6 or Asp7. Interaction of the zinc ion with this site involves His6, thereby withdrawing it from the interaction pattern observed in the non-modified peptide. This event was found to stimulate dimerization of peptide chains through the (11)EVHH(14) site, where the zinc ion is coordinated by the two pairs of Glu11 and His14 in the two peptide subunits. The proposed molecular mechanism of zinc-induced dimerization could contribute to the understanding of initiation of pathological Aβ aggregation, and the (11)EVHH(14) tetrapeptide can be considered as a promising drug target for the prevention of amyloidogenesis.
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov street 32, 119991 Moscow, Russia. aamakarov@eimb.ru.
authors.forename: Alexandra A
authors.initials: AA
authors.lastname: Kulikova
authors.forename: Philipp O
authors.initials: PO
authors.lastname: Tsvetkov
authors.forename: Maria I
authors.initials: MI
authors.lastname: Indeykina
authors.forename: Igor A
authors.initials: IA
authors.lastname: Popov
authors.forename: Sergey S
authors.initials: SS
authors.lastname: Zhokhov
authors.forename: Andrey V
authors.initials: AV
authors.lastname: Golovin
authors.forename: Vladimir I
authors.initials: VI
authors.lastname: Polshakov
authors.forename: Sergey A
authors.initials: SA
authors.lastname: Kozin
authors.forename: Evgeny
authors.initials: E
authors.lastname: Nudler
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Makarov
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D001665:Binding Sites; D007477:Ions / Q000378:metabolism; D008954:Models, Biological; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D012694:Serine / Q000378:metabolism; D013816:Thermodynamics; D015032:Zinc / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D007477:Ions; D012694:Serine; D015032:Zinc