The present proposal aims to study the relationships existing between protein structural dynamics and pathological aggregation of the multidomain N-terminal part of the polyglutamine (polyQ) protein ataxin-3. By means of an integrated approach combining advanced NMR and computational techniques, the applicant plans to investigate low frequencies native-like states responsible of aberrant protein-protein interactions leading to first amyloid aggregates. These species in AT3 predominantly involve the globular structured N-terminal domain and are polyQ independent. Results of this project will boost the knowledge related to the first misfolding events leading to AT3 pathological aggregation as well as our understanding on subtle misfolding events triggering protein aggregation of folded globular proteins.
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