Progress in FY2017 was in the following areas: LOW COMPLEXITY SEQUENCES. In collaboration with Prof. Steven McKnight (UT Southwestern Medical Center) and his colleagues, we have completed an extensive set of solid state NMR and electron microscopy measurements on fibrils formed by the low complexity domain of the fused in sarcoma protein (FUS-LC). From these data, we have determined a full molecular structure for FUS-LC fibrils, representing the first structure determination of a low complexity protein assembly. Interestingly, the fibril core is formed by a specific 57-residue segment within the 214-residue FUS-LC sequence, despite the overall self-similarity and repetitive nature of the sequence. A paper describing these results has been accepted for publication in Cell. In related work, we have used solid state NMR to show that a critical aspartate residue in the low-complexity domain of the hnRNPA2 protein (Asp290) residues in an in-register, parallel cross-beta structure in hnRNPA2 fibrils. This result explains why mutation of this aspartate residue to valine leads to frontotemporal dementia and amyotrophic lateral sclerosis, by stabilizing the cross-beta fibril structure. A paper describing these results is in preparation.
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