On the mechanism of nonspecific inhibitors of protein aggregation: dissecting the interactions of Î±-synuclein with congo red and lacmoid
Lendel, C. and Bertoncini, C.W. and Cremades, N. and Waudby, Christopher A. and Vendruscolo, M. and Dobson, C.M. and Schenk, D. and Christodoulou, John and Toth, G. (2009) On the mechanism of nonspecific inhibitors of protein aggregation: dissecting the interactions of Î±-synuclein with congo red and lacmoid. Biochemistry 48 (35), pp. 8322-8334. ISSN 0006-2960.
Increasing evidence links the misfolding and aberrant self-assembly of proteins with the molecular events that underlie a 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 α-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 α-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.
|School:||Birkbeck Schools and Departments > School of Science > Biological Sciences|
|Research Centre:||Structural Molecular Biology, Institute of (ISMB)|
|Date Deposited:||04 Aug 2010 14:09|
|Last Modified:||06 Dec 2016 10:48|
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