Structural and mechanistic basis behind the inhibitory interaction of PcTS on alpha-synuclein amyloid fibril formation.
The identification of aggregation inhibitors and the investigation of their mechanism of action are fundamental in the quest to mitigate the pathological consequences of amyloid formation. Here, characterization of the structural and mechanistic basis for the antiamyloidogenic effect of phthalocyanine tetrasulfonate (PcTS) on alpha-synuclein (AS) allowed us to demonstrate that specific aromatic interactions are central for ligand-mediated inhibition of amyloid formation. We provide evidence indicating that the mechanism behind the antiamyloidogenic effect of PcTS is correlated with the trapping of prefibrillar AS species during the early stages of the assembly process. By using NMR spectroscopy, we have located the primary binding region for PcTS to a specific site in the N terminus of AS, involving the amino acid Tyr-39 as the anchoring residue. Moreover, the residue-specific structural characterization of the AS-PcTS complex provided the basis for the rational design of nonamyloidogenic species of AS, highlighting the role of aromatic interactions in driving AS amyloid assembly. A comparative analysis with other proteins involved in neurodegenerative disorders reveals that aromatic recognition interfaces might constitute a key structural element to target their aggregation pathways. These findings emphasize the use of aggregation inhibitors as molecular probes to assess structural and toxic mechanisms related to amyloid formation and the potential of small molecules as therapeutics for amyloid-related pathologies.
Lamberto
Gonzalo R
GR
Instituto de Biología Molecular y Celular de Rosario, Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad Nacional de Rosario, Suipacha 531, S2002LRK Rosario, Argentina.
Binolfi
Andrés
A
Orcellet
María L
ML
Bertoncini
Carlos W
CW
Zweckstetter
Markus
M
Griesinger
Christian
C
Fernández
Claudio O
CO
D000682:Amyloid / Q000096:biosynthesis*; D001665:Binding Sites; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D015335:Molecular Probes; D055503:Protein Multimerization; D051844:alpha-Synuclein / Q000037:antagonists & inhibitors*
D000682:Amyloid; D007211:Indoles; D015335:Molecular Probes; D051844:alpha-Synuclein; C028418:tetrasulfophthalocyanine