Functional and dynamic polymerization of the ALS-linked protein TDP-43 antagonizes its pathologic aggregation
Nat Commun. 2017-06-29; 8(1):
DOI: 10.1038/s41467-017-00062-0
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1. Nat Commun. 2017 Jun 29;8(1):45. doi: 10.1038/s41467-017-00062-0.
Functional and dynamic polymerization of the ALS-linked protein TDP-43
antagonizes its pathologic aggregation.
Afroz T(1), Hock EM(1), Ernst P(2), Foglieni C(3), Jambeau M(1), Gilhespy LAB(1),
Laferriere F(1), Maniecka Z(1), Plückthun A(2), Mittl P(2), Paganetti P(3),
Allain FHT(4), Polymenidou M(5).
Author information:
(1)Institute of Molecular Life Sciences, University of Zurich,
Winterthurerstrasse 190, CH-8057, Zurich, Switzerland.
(2)Department of Biochemistry, University of Zurich, Winterthurerstrasse 190,
CH-8057, Zurich, Switzerland.
(3)Laboratory for Biomedical Neurosciences, Neurocenter of Southern Switzerland,
Via Tesserete 46, CH-6900, Lugano, Switzerland.
(4)Institute of Molecular Biology and Biophysics, ETH Zurich, CH-8093, Zurich,
Switzerland.
(5)Institute of Molecular Life Sciences, University of Zurich,
Winterthurerstrasse 190, CH-8057, Zurich, Switzerland.
.
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.
DOI: 10.1038/s41467-017-00062-0
PMCID: PMC5491494
PMID: 28663553 [Indexed for MEDLINE]