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On the Mechanism of Nonspecific Inhibitors of Protein Aggregation: Dissecting the Interactions of alpha-Synuclein with Congo Red and Lacmoid

Lendel, C; Bertoncini, CW; Cremades, N; Waudby, CA; Vendruscolo, M; Dobson, CM; Schenk, D; ... Toth, G; + view all (2009) On the Mechanism of Nonspecific Inhibitors of Protein Aggregation: Dissecting the Interactions of alpha-Synuclein with Congo Red and Lacmoid. BIOCHEMISTRY-US , 48 (35) 8322 - 8334. 10.1021/bi901285x.

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Abstract

Increasing evidence links the misfolding and aberrant self-assembly of proteins with the molecular events that underlie it range of neurodegenerative diseases, yet the mechanistical details of these processes are still poorly understood. The fact that many of these proteins are intrinsically unstructured makes it particularly challenging to develop strategies for discovering small molecule inhibitors of their aggregation. We present here a broad biophysical approach that enables us to characterize the mechanisms of interaction between alpha-synuclein, a protein whose aggregation is closely connected with Parkinson's disease, and two small molecules, Congo red and Lacmoid, which inhibit its fibrillization. Both compounds are found to interact with the N-terminal and central regions of the monomeric protein although with different binding mechanisms and affinities. The differences can be attributed to the chemical nature of the compounds as well as their abilities to self-associate. We, further show that alpha-synuclein binding and aggregation inhibition are mediated by small oligomeric species of the compounds that interact with distinct regions of the monomeric protein. These findings provide potential explanations of the nonspecific antiamyloid effect observed for these compounds as well as important mechanistical information for future drug discovery efforts targeting the misfolding and aggregation of intrinsically unstructured proteins.

Type: Article
Title: On the Mechanism of Nonspecific Inhibitors of Protein Aggregation: Dissecting the Interactions of alpha-Synuclein with Congo Red and Lacmoid
DOI: 10.1021/bi901285x
Keywords: SMALL-MOLECULE INHIBITORS, AMYLOID FIBRIL FORMATION, NMR-SPECTROSCOPY, PARKINSONS-DISEASE, BETA-SYNUCLEIN, PROTONLESS NMR, IN-VITRO, BINDING, NEURODEGENERATION, OLIGOMERIZATION
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology
URI: http://discovery.ucl.ac.uk/id/eprint/192084
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