5X4F

Solution Structure of the N-terminal Domain of TDP-43

Summary for 5X4F

• Entry DOI: 10.2210/pdb5x4f/pdb
• NMR Information: BMRB: 36060
• Descriptor: TAR DNA-binding protein 43 (1 entity in total)
• Functional Keywords: dimerization, dna binding protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 8502.39

Authors

Jiang, L.-L.,Xue, W.,Hu, H.-Y. (deposition date: 2017-02-13, release date: 2017-08-16, Last modification date: 2024-05-15)

Primary citation

Jiang, L.L.,Xue, W.,Hong, J.Y.,Zhang, J.T.,Li, M.J.,Yu, S.N.,He, J.H.,Hu, H.Y.
The N-terminal dimerization is required for TDP-43 splicing activity.
Sci Rep, 7:6196-6196, 2017

PubMed Abstract: TDP-43 is a nuclear factor that functions in promoting pre-mRNA splicing. Deletion of the N-terminal domain (NTD) and nuclear localization signal (NLS) (i.e., TDP-35) results in mislocalization to cytoplasm and formation of inclusions. However, how the NTD functions in TDP-43 activity and proteinopathy remains largely unknown. Here, we studied the structure and function of the NTD in inclusion formation and pre-mRNA splicing of TDP-43 by using biochemical and biophysical approaches. We found that TDP-43 NTD forms a homodimer in solution in a concentration-dependent manner, and formation of intermolecular disulfide results in further tetramerization. Based on the NMR structure of TDP-43 NTD, the dimerization interface centered on Leu71 and Val72 around the β7-strand was defined by mutagenesis and size-exclusion chromatography. Cell experiments revealed that the N-terminal dimerization plays roles in protecting TDP-43 against formation of cytoplasmic inclusions and enhancing pre-mRNA splicing activity of TDP-43 in nucleus. This study may provide mechanistic insights into the physiological function of TDP-43 and its related proteinopathies.

PubMed: 28733604
DOI: 10.1038/s41598-017-06263-3

Experimental method

SOLUTION NMR