Structure of Protein Aggregates by Solid State NMR

描述（由申请人提供）：本研究的长期目标是对与人类疾病相关的蛋白质聚集和纤维化进行详细的原子分辨率结构和功能理解，主要是对α-突触核蛋白进行研究。与早发性帕金森病（PD）相关的野生型α-突触核蛋白及其突变体（A30 P、E46 K和A53 T）将在几种结构状态下进行检查，包括原纤维、原纤维和膜相关复合物。我们建议，这些结构的化学细节决定了α-突触核蛋白的自然生理功能，并在突变体和/或环境压力下，有助于PD病理。此外，我们提出，几种结构状态之间的转换是突触核蛋白的一个基本特征，这种结构的可塑性可能是神经元的发育和维护所必需的。为了研究这些结构，魔角旋转（MAS）固态NMR（SSNMR）实验将采用，阐明构象和动力学的细节，是无法访问其他实验技术。

DESCRIPTION (provided by applicant): The long-term objective of this research is to develop a detailed, atomic-resolution structural and functional understanding of protein aggregation and fibrillation relevant to human disease, principally with studies of alpha-synuclein. Wild type alpha-synuclein and its mutants (A30P, E46K and A53T) associated with early- onset Parkinson's disease (PD) will be examined in several structural states, including protofibrils, fibrils and membrane-associated complexes. We propose that the chemical details of these structures determine the natural physiological function of alpha-synuclein and, in the mutants and/or under environmental stress, contribute to PD pathology. Moreover, we propose that conversion among several structural states is an essential feature of synucleins; this structural plasticity is likely to be required for neuronal development and maintenance. To examine these structures, magic-angle spinning (MAS) solid-state NMR (SSNMR) experiments will be employed, elucidating details of conformation and dynamics that are inaccessible to other experimental techniques.