5MDI

Crystal structure of TDP-43 N-terminal domain at 2.1 A resolution

Summary for 5MDI

• Entry DOI: 10.2210/pdb5mdi/pdb
• Descriptor: TAR DNA-binding protein 43, ACETATE ION (3 entities in total)
• Functional Keywords: rna binding proteins, dynamic polymerization, als, protein aggregation, rna binding protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 22949.82

Authors

Afroz, T.,Hock, E.-M.,Ernst, P.,Foglieni, C.,Jambeau, M.,Gilhespy, L.,Laferriere, F.,Maniecka, Z.,Plueckthun, A.,Mittl, P.,Paganetti, P.,Allain, F.H.T.,Polymenidou, M. (deposition date: 2016-11-11, release date: 2017-07-05, Last modification date: 2024-11-13)

Primary citation

Afroz, T.,Hock, E.M.,Ernst, P.,Foglieni, C.,Jambeau, M.,Gilhespy, L.A.B.,Laferriere, F.,Maniecka, Z.,Pluckthun, A.,Mittl, P.,Paganetti, P.,Allain, F.H.T.,Polymenidou, M.
Functional and dynamic polymerization of the ALS-linked protein TDP-43 antagonizes its pathologic aggregation.
Nat Commun, 8:45-45, 2017

PubMed Abstract: TDP-43 is a primarily nuclear RNA-binding protein, whose abnormal phosphorylation and cytoplasmic aggregation characterizes affected neurons in patients with amyotrophic lateral sclerosis and frontotemporal dementia. Here, we report that physiological nuclear TDP-43 in mouse and human brain forms homo-oligomers that are resistant to cellular stress. Physiological TDP-43 oligomerization is mediated by its N-terminal domain, which can adopt dynamic, solenoid-like structures, as revealed by a 2.1 Å crystal structure in combination with nuclear magnetic resonance spectroscopy and electron microscopy. These head-to-tail TDP-43 oligomers are unique among known RNA-binding proteins and represent the functional form of the protein in vivo, since their destabilization results in loss of alternative splicing regulation of known neuronal RNA targets. Our findings indicate that N-terminal domain-driven oligomerization spatially separates the adjoining highly aggregation-prone, C-terminal low-complexity domains of consecutive TDP-43 monomers, thereby preventing low-complexity domain inter-molecular interactions and antagonizing the formation of pathologic aggregates.TDP-43 aggregation is observed in amyotrophic lateral sclerosis. Here the authors combine X-ray crystallography, nuclear magnetic resonance and electron microscopy studies and show that physiological oligomerization of TDP-43 is mediated through its N-terminal domain, which forms functional and dynamic oligomers antagonizing pathologic aggregation.

PubMed: 28663553
DOI: 10.1038/s41467-017-00062-0

Experimental method

X-RAY DIFFRACTION (2.1 Å)