Three-Dimensional Structure of RNA-Binding Protein TLS Co-Crystallized with Biotinylated Isoxazole
RNA-binding protein TLS with specific mutations forms insoluble precipitates in motor neurons causing neuronal degenerative diseases like amyotrophic lateral sclerosis (ALS), and frontotemporal dementia. TLS at high concentration around 10 mg/ml is prone to be precipitated even without any mutation. The mutation on TLS is supposed to induce more precipitation than the wild type with uncovered molecular mechanism. Specific protein precipitation is one of major causes for the neuronal diseases like the Alzheimer disease with amyloid formations. Identification of a trigger of the precipitation formation is a key event at developing the therapeutics against these diseases. Screening candidate compounds from a chemical library to stimulate mouse embryonic stem cells into cardiomyocytes identified isoxazole, its relative compounds containing the COX-2 inhibitor and β lactamase-resistant antibiotics. Its derivative, biotinylated isoxazole (b-isox), was serendipitously found to be precipitated with divergent RNA-binding proteins through their low complexity domains. The b-isox precipitation of RNA-binding proteins should be a model system for formation of insoluble precipitates at neuronal degenerative diseases. We confirmed the precipitation of TLS with b-isox and analyzed the co-crystal formation. In silico analysis presents a model of crystallization of b-isox forming the β strand structure with wavy repetitive valleys. The valleys of the β sheet capture the unstructured LC domains of TLS and force them into also β strand shapes. This model sheds light on flexible feature of the LC domain that well fits the valleys of the b-isox crystals. This should be one major reason why various LC domains are involves in formation of insoluble precipitates, suggesting molecular mechanism for neurodegenerative disorders.
Three-Dimensional Structure of RNA-Binding Protein TLS Co-Crystallized with Biotinylated Isoxazole, Biomedical Sciences.
Vol. 2, No. 1,
2016, pp. 1-10.
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