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Atomic-level evidence for packing and positional amyloid polymorphism by segment from TDP-43 RRM2
Elizabeth L Guenther1,2,3,4, Peng Ge5, Hamilton Trinh1,4,6
1Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA, USA.
Nature Structural & Molecular Biology
|March 14, 2018
Summary
Amyloid proteins form diverse structures in neurodegenerative diseases. Researchers studied a human TAR DNA-binding protein 43 (TDP-43) segment, revealing multiple amyloid polymorphs and backbone conformations at the molecular level.
Area of Science:
- Structural biology
- Neurodegenerative disease research
- Biochemistry
Background:
- Amyloid proteins are key features of neurodegenerative diseases.
- Understanding the diverse molecular conformations (polymorphs) of amyloid proteins is crucial but challenging.
- Human TAR DNA-binding protein 43 (TDP-43) is implicated in neurodegenerative conditions.
Purpose of the Study:
- To investigate the polymorphic capabilities of amyloid aggregation using a TDP-43 segment as a model.
- To characterize the molecular structures formed by a specific TDP-43 segment (247DLIIKGISVHI257).
Main Methods:
- X-ray diffraction
- Microelectron diffraction (MicroED)
- Single-particle cryo-electron microscopy (cryo-EM)
Main Results:
- The TDP-43 segment formed numerous amyloid polymorphs.
- Seven distinct steric zipper interfaces belonging to five symmetry classes were identified.
- Three different backbone conformations were observed, contributing to the segment's polymorphism.
Conclusions:
- The studied TDP-43 segment exhibits significant polymorphic potential.
- This molecular-level understanding of amyloid polymorphism can inform neurodegenerative disease research.
- Diverse fibril structures arise from the inherent polymorphic nature of amyloidogenic protein segments.
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