title: Binding of TDP-43 to the 3'UTR of its cognate mRNA enhances its solubility.
abstract: TAR DNA binding protein of 43 kDa (TDP-43) has been implicated in the pathogenesis of a broad range of neurodegenerative diseases termed TDP-43 proteinopathies, which encompass a spectrum of diseases ranging from amyotrophic lateral sclerosis to frontotemporal dementia. Pathologically misfolded and aggregated forms of TDP-43 are found in cytoplasmic inclusion bodies of affected neurons in these diseases. The mechanism by which TDP-43 misfolding causes disease is not well-understood. Current hypotheses postulate that the TDP-43 aggregation process plays a major role in pathogenesis. We amplify that hypothesis and suggest that binding of cognate ligands to TDP-43 can stabilize the native functional state of the protein and ameliorate aggregation. We expressed recombinant TDP-43 containing an N-terminal Venus yellow fluorescent protein tag in Escherichia coli and induced its aggregation by altering solvent salt concentrations and examined the extent to which various oligonucleotide molecules affect its aggregation in vitro using aggregation-induced turbidity assays. We show that vYFP-TDP-43 binding to its naturally occurring RNA target that comprises a sequence on the 3'UTR region of its mRNA improves its solubility, suggesting interplay among TDP-43 solubility, oligonucleotide binding, and TDP-43 autoregulation.
authors.affiliation: Department of Medical Biophysics, University of Toronto , Toronto, Ontario M5G 1L7, Canada.
authors.forename: Yulong
authors.initials: Y
authors.lastname: Sun
authors.forename: Pharhad E
authors.initials: PE
authors.lastname: Arslan
authors.forename: Amy
authors.initials: A
authors.lastname: Won
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Yip
authors.forename: Avi
authors.initials: A
authors.lastname: Chakrabartty
mesh_terms: D020413:3' Untranslated Regions; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D004926:Escherichia coli / Q000235:genetics; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D055503:Protein Multimerization; D012333:RNA, Messenger / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; D008164:Luminescent Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D011994:Recombinant Proteins; C054562:yellow fluorescent protein, Bacteria