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PMID:15826655

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Citation

Ayala, YM, Pantano, S, D'Ambrogio, A, Buratti, E, Brindisi, A, Marchetti, C, Romano, M and Baralle, FE (2005) Human, Drosophila, and C.elegans TDP43: nucleic acid binding properties and splicing regulatory function. J. Mol. Biol. 348:575-88

Abstract

TAR DNA binding protein (TDP43), a highly conserved heterogeneous nuclear ribonucleoprotein, was found to down-regulate splicing of the exon 9 cystic fibrosis transmembrane conductance regulator (CFTR) through specific binding to a UG-rich polymorphic region upstream of the 3' splice site. Despite the emergence of new information regarding the protein's nuclear localization and splicing regulatory activity, TDP43's role in cells remains elusive. To investigate the function of human TDP43 and its homologues, we cloned and characterized the proteins from Drosophila melanogaster and Caenorhabditis elegans. The proteins from human, fly, and worm show striking similarities in their nucleic acid binding specificity. We found that residues at two different positions, which show a strong conservation among TDP43 family members, are linked to the tight recognition of the target sequence. Our three-dimensional model of TDP43 in complex with a (UG)(m) sequence predicts that these residues make amino acid side-chain to base contacts. Moreover, our results suggest that Drosophila TDP43 is comparable to human TDP43 in regulating exon splicing. On the other hand, C.elegans TDP43 has no effect on exon recognition. TDP43 from C.elegans lacks the glycine-rich domain found at the carboxy terminus of the other two homologues. Mutants of human and fly TDP43 devoid of the C-terminal domain are likewise unable to affect splicing. Our studies suggest that the glycine-rich domain is essential for splicing regulation by human and fly TDP43.

Links

PubMed Online version:10.1016/j.jmb.2005.02.038

Keywords

Amino Acid Sequence; Animals; Base Sequence; Caenorhabditis elegans/metabolism; Cystic Fibrosis Transmembrane Conductance Regulator/genetics; Cystic Fibrosis Transmembrane Conductance Regulator/metabolism; DNA-Binding Proteins/chemistry; DNA-Binding Proteins/genetics; DNA-Binding Proteins/metabolism; Drosophila melanogaster/metabolism; Humans; Macromolecular Substances; Models, Molecular; Molecular Sequence Data; Mutagenesis, Site-Directed; Nucleic Acids/metabolism; Protein Binding; Protein Structure, Tertiary; RNA Splicing; Recombinant Fusion Proteins/genetics; Recombinant Fusion Proteins/metabolism; Sequence Alignment; Sequence Analysis, Protein

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

CAEEL:TADBP

enables

GO:0003727: single-stranded RNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

DROME:O97468

involved_in

GO:0033119: negative regulation of RNA splicing

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:O97468

enables

GO:0003697: single-stranded DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

DROME:O97468

enables

GO:1990605: GU repeat RNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

DROME:O97469

involved_in

GO:0033119: negative regulation of RNA splicing

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:O97469

enables

GO:0003697: single-stranded DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

DROME:O97469

enables

GO:1990605: GU repeat RNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

DROME:Q8SXP8

involved_in

GO:0033119: negative regulation of RNA splicing

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:Q8SXP8

enables

GO:0003697: single-stranded DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

DROME:Q8SXP8

enables

GO:1990605: GU repeat RNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

DROME:Q9W1I0

involved_in

GO:0033119: negative regulation of RNA splicing

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:Q9W1I0

enables

GO:0003697: single-stranded DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

DROME:Q9W1I0

enables

GO:1990605: GU repeat RNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

CAEEL:D0VWM8

enables

GO:0003727: single-stranded RNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

Notes

See also

References

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