title: Molecular properties of TAR DNA binding protein-43 fragments are dependent upon its cleavage site.
abstract: Aggregation of TAR DNA binding protein-43 (TDP-43) is a hallmark feature of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Under pathogenic conditions, abnormal cleavage of TDP-43 produces the phosphorylated C-terminal fragments (CTFs), which are enriched in neuronal inclusions; however, molecular properties of those TDP-43 fragments remain to be characterized. Here we show distinct degrees of solubility and phosphorylation among fragments truncated at different sites of TDP-43. Truncations were tested mainly within a second RNA recognition motif (RRM2) of TDP-43; when the truncation site was more C-terminal in an RRM2 domain, a TDP-43 CTF basically became less soluble and more phosphorylated in differentiated Neuro2a cells. We also found that cleavage at the third β-strand in RRM2 leads to the formation of SDS-resistant soluble oligomers. Molecular properties of TDP-43 fragments thus significantly depend upon its cleavage site, which might reflect distinct molecular pathologies among sub-types of TDP-43 proteinopathies.
authors.affiliation: Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, Wako, Saitama, Japan. furukawa@chem.keio.ac.jp
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Furukawa
authors.forename: Kumi
authors.initials: K
authors.lastname: Kaneko
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Nukina
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D021381:Protein Transport; D059748:Proteolysis; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012995:Solubility
chemical_list: D004268:DNA-Binding Proteins; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins