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The TDP-43 N-terminal domain structure at high resolution
- Source :
- Digital.CSIC. Repositorio Institucional del CSIC, instname
- Publication Year :
- 2016
- Publisher :
- Blackwell Publishing, 2016.
-
Abstract
- Transactive response DNA-binding protein 43 kDa (TDP-43) is an RNA transporting and processing protein whose aberrant aggregates are implicated in neurodegenerative diseases. The C-terminal domain of this protein plays a key role in mediating this process. However, the N-terminal domain (residues 1-77) is needed to effectively recruit TDP-43 monomers into this aggregate. In the present study, we report, for the first time, the essentially complete (1) H, (15) N and (13) C NMR assignments and the structure of the N-terminal domain determined on the basis of 26 hydrogen-bond, 60 torsion angle and 1058 unambiguous NOE structural restraints. The structure consists of an ¿-helix and six ß-strands. Two ß-strands form a ß-hairpin not seen in the ubiquitin fold. All Pro residues are in the trans conformer and the two Cys are reduced and distantly separated on the surface of the protein. The domain has a well defined hydrophobic core composed of F35, Y43, W68, Y73 and 17 aliphatic side chains. The fold is topologically similar to the reported structure of axin 1. The protein is stable and no denatured species are observed at pH 4 and 25 °C. At 4 kcal·mol(-1) , the conformational stability of the domain, as measured by hydrogen/deuterium exchange, is comparable to ubiquitin (6 kcal·mol(-1) ). The ß-strands, ¿-helix, and three of four turns are generally rigid, although the loop formed by residues 47-53 is mobile, as determined by model-free analysis of the (15) N{(1) H}NOE, as well as the translational and transversal relaxation rates.
- Subjects :
- 0301 basic medicine
Models, Molecular
Protein Folding
Magnetic Resonance Spectroscopy
hydrogen/deuterium exchange
Protein domain
Molecular Sequence Data
DNA-binding protein 43 (TDP-43)
Biochemistry
Protein Structure, Secondary
03 medical and health sciences
0302 clinical medicine
Protein structure
protein dynamics
protein structure
TAR
Animals
Humans
Amino Acid Sequence
Molecular Biology
Conformational isomerism
ALS/FTLD
Binding Sites
Chemistry
Deuterium Exchange Measurement
Hydrogen Bonding
Cell Biology
Nuclear magnetic resonance spectroscopy
computer.file_format
Hydrogen-Ion Concentration
Protein Data Bank
Peptide Fragments
Protein Structure, Tertiary
Crystallography
030104 developmental biology
Spectrometry, Fluorescence
Cyclic nucleotide-binding domain
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Protein folding
Hydrogen–deuterium exchange
computer
030217 neurology & neurosurgery
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Digital.CSIC. Repositorio Institucional del CSIC, instname
- Accession number :
- edsair.doi.dedup.....eaa2fec9b323fcc62742a4d08e2aee60