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Transition Metal Ion FRET-Based Probe to Study Cu(II)-Mediated Amyloid-ß Ligand Binding.
Wu, Ri; Svingou, Despoina; Metternich, Jonas B; Benzenberg, Lukas R; Zenobi, Renato.
Afiliación
  • Wu R; Laboratory of Organic Chemistry, Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland.
  • Svingou D; Laboratory of Organic Chemistry, Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland.
  • Metternich JB; Laboratory of Organic Chemistry, Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland.
  • Benzenberg LR; Laboratory of Organic Chemistry, Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland.
  • Zenobi R; Laboratory of Organic Chemistry, Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland.
J Am Chem Soc ; 146(3): 2102-2112, 2024 01 24.
Article en En | MEDLINE | ID: mdl-38225538
ABSTRACT
Recent therapeutic strategies suggest that small peptides can act as aggregation inhibitors of monomeric amyloid-ß (Αß) by inducing structural rearrangements upon complexation. However, characterizing the binding events in such dynamic and transient noncovalent complexes, especially in the presence of natively occurring metal ions, remains a challenge. Here, we deploy a combined transition metal ion Förster resonance energy transfer (tmFRET) and native ion mobility-mass spectrometry (IM-MS) approach to characterize the structure of mass- and charge-selected Aß complexes with Cu(II) ions (a quencher) and a potential aggregation inhibitor, a small neuropeptide named leucine enkephalin (LE). We show conformational changes of monomeric Αß species upon Cu(II)-binding, indicating an uncoiled N-terminus and a close interaction between the C-terminus and the central hydrophobic region. Furthermore, we introduce LE labeled at the N-terminus with a metal-chelating agent, nitrilotriacetic acid (NTA). This allows us to employ tmFRET to probe the binding even in low-abundance and transient Aß-inhibitor-metal ion complexes. Complementary intramolecular distance and global shape information from tmFRET and native IM-MS, respectively, confirmed Cu(II) displacement toward the N-terminus of Αß, which discloses the binding region and the inhibitor's orientation.
Asunto(s)

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Elementos de Transición / Transferencia Resonante de Energía de Fluorescencia Idioma: En Revista: J Am Chem Soc Año: 2024 Tipo del documento: Article País de afiliación: Suiza

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Elementos de Transición / Transferencia Resonante de Energía de Fluorescencia Idioma: En Revista: J Am Chem Soc Año: 2024 Tipo del documento: Article País de afiliación: Suiza