Structure determination of proteins and protein aggregates by magic-angle spinning solid-state NMR

Solid state NMR (SSNMR) is a structure determination technique uniquely suited to study protein aggregates and fibrils. Unlike solution NMR or X-ray crystallography, SSNMR can obtain atomic resolution structural information on samples of protein fibrils which are insoluble and do not produce X-ray diffracting crystals. As SSNMR begins to realize this potential, new structure determination techniques will be important in enable SSNMR to investigate ever larger and more complicated systems. Alpha-synuclein (AS) is the primary protein component of Lewy bodies, the pathological hallmark of Parkinson’s disease. The structure of AS in its fibril form is unknown, as is the mechanism by which it contributes to neurodegeneration. At 140 residues, AS is much larger than other fibril systems that have been studied by SSNMR. To solve the structure of AS fibrils will require combining new pulse sequences with advanced isotopic labeling schemes, and novel structure calculation methods. The techniques developed in this study will be useful in the study of other protein aggregates, as well as membrane proteins and complexes, for which SSNMR is the structure determination method of choice