National Institutes of Health/National Institute on Aging (NIH/NIA)
AG061797
米国
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
GM094357
米国
引用
ジャーナル: Nat Commun / 年: 2021 タイトル: Cryo-EM structure of amyloid fibrils formed by the entire low complexity domain of TDP-43. 著者: Qiuye Li / W Michael Babinchak / Witold K Surewicz / 要旨: Amyotrophic lateral sclerosis and several other neurodegenerative diseases are associated with brain deposits of amyloid-like aggregates formed by the C-terminal fragments of TDP-43 that contain the ...Amyotrophic lateral sclerosis and several other neurodegenerative diseases are associated with brain deposits of amyloid-like aggregates formed by the C-terminal fragments of TDP-43 that contain the low complexity domain of the protein. Here, we report the cryo-EM structure of amyloid formed from the entire TDP-43 low complexity domain in vitro at pH 4. This structure reveals single protofilament fibrils containing a large (139-residue), tightly packed core. While the C-terminal part of this core region is largely planar and characterized by a small proportion of hydrophobic amino acids, the N-terminal region contains numerous hydrophobic residues and has a non-planar backbone conformation, resulting in rugged surfaces of fibril ends. The structural features found in these fibrils differ from those previously found for fibrils generated from short protein fragments. The present atomic model for TDP-43 LCD fibrils provides insight into potential structural perturbations caused by phosphorylation and disease-related mutations.
A: Isoform 2 of TAR DNA-binding protein 43 B: Isoform 2 of TAR DNA-binding protein 43 C: Isoform 2 of TAR DNA-binding protein 43 D: Isoform 2 of TAR DNA-binding protein 43 E: Isoform 2 of TAR DNA-binding protein 43