Phosphorylation of Ser8 promotes zinc-induced dimerization of the amyloid-β metal-binding domain.

نویسندگان

  • Alexandra A Kulikova
  • Philipp O Tsvetkov
  • Maria I Indeykina
  • Igor A Popov
  • Sergey S Zhokhov
  • Andrey V Golovin
  • Vladimir I Polshakov
  • Sergey A Kozin
  • Evgeny Nudler
  • Alexander A Makarov
چکیده

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.

برای دانلود رایگان متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Zinc-induced dimerization of the amyloid-β metal-binding domain 1-16 is mediated by residues 11-14.

Analysis of complex formation between amyloid-β fragments using surface plasmon resonance biosensing and electrospray mass spectrometry reveals that region 11-14 mediates zinc-induced dimerization of amyloid-β and may serve as a potential drug target for preventing development and progression of Alzheimer's disease.

متن کامل

The English (H6R) familial Alzheimer's disease mutation facilitates zinc-induced dimerization of the amyloid-β metal-binding domain.

Interaction of Zn(2+) with the metal-binding domain of the English (H6R) amyloid-β mutant results in the formation of peptide dimers. The mutation causes the exclusion of His6 from the zinc chelation pattern observed in the intact domain and triggers the assembly of the dimers via zinc ions coordinated by (11)EVHH(14) fragments.

متن کامل

Polarization effect of zinc on the region 1-16 of amyloid-beta peptide: a molecular dynamics study

Zinc is found saturated in the deposited Amyloid-beta ( β A ) peptide plaques in Alzheimer’s disease (AD) patients’ brains. Zinc binding to β A promotes aggregations, including the toxic soluble β A species. Up to now, only the region 1-16 of β A complexed with Zinc ( 16 1− β A -Zn ) is defined structurally in experiment, requiring an efficient theoretical method to present the interaction betw...

متن کامل

Minimal Zn(2+) binding site of amyloid-β.

Zinc-induced aggregation of amyloid-β peptide (Aβ) is a hallmark molecular feature of Alzheimer's disease. Here we provide direct thermodynamic evidence that elucidates the role of the Aβ region 6-14 as the minimal Zn(2+) binding site wherein the ion is coordinated by His(6), Glu(11), His(13), and His(14). With the help of isothermal titration calorimetry and quantum mechanics/molecular mechani...

متن کامل

Molecular mechanisms of heavy metal homeostasis in flies and humans

Metal-responsive transcription factor-1 (MTF-1) is an evolutionarily conserved zinc finger protein that activates transcription in response to heavy metals such as Zn(II), Cd(II) and Cu(I). The DNA-binding domain of MTF-1 recognizes a specific DNA sequence termed the metal response element (MRE), located in the promoter/enhancer region of its target genes. Here we show that human MTF-1 forms ho...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

عنوان ژورنال:
  • Molecular bioSystems

دوره 10 10  شماره 

صفحات  -

تاریخ انتشار 2014