a major role for side-chain polyglutamine hydrogen bonding in irreversible ataxin-3 aggregation受到多麸醯胺酸侧链的主要作用氢键在不可逆ataxin-3聚合.pdfVIP

A Major Role for Side-Chain Polyglutamine Hydrogen Bonding in Irreversible Ataxin-3 Aggregation 1. 1. 2 3 1 Antonino Natalello , Anna Maria Frana , Annalisa Relini , Alessandra Apicella , Gaetano Invernizzi , 3 2 1 1 1 Carlo Casari , Alessandra Gliozzi , Silvia Maria Doglia *, Paolo Tortora *, Maria Elena Regonesi 1 Department of Biotechnologies and Biosciences, University of Milano-Bicocca, Milan, Italy, 2 Department of Physics, University of Genoa, Genoa, Italy, 3 Energy Department, Polythechnic of Milan, Milan, Italy Abstract The protein ataxin-3 consists of an N-terminal globular Josephin domain (JD) and an unstructured C-terminal region containing a stretch of consecutive glutamines that triggers the neurodegenerative disorder spinocerebellar ataxia type 3, when it is expanded beyond a critical threshold. The disease results from misfolding and aggregation, although the pathway and structure of the aggregation intermediates are not fully understood. In order to provide insight into the mechanism of the process, we monitored the aggregation of a normal (AT3Q24) ataxin-3, an expanded (AT3Q55) ataxin-3, and the JD in isolation. We observed that all of them aggregated, although the latter did so at a much slower rate. Furthermore, the expanded AT3Q55 displayed a substantially different behavior with respect to the two other variants in that at the latest stages of the process it was the only one that did the following: i) lost its reactivity towards an anti-