Atomic-level evidence for packing and positional amyloid polymorphism by segment from TDP-43 RRM2

Elizabeth L Guenther; Peng Ge; Hamilton Trinh; Michael R Sawaya; Duilio Cascio; David R Boyer; Tamir Gonen; Z Hong Zhou; David S Eisenberg

doi:10.1038/s41594-018-0045-5

Atomic-level evidence for packing and positional amyloid polymorphism by segment from TDP-43 RRM2

Nat Struct Mol Biol. 2018 Apr;25(4):311-319. doi: 10.1038/s41594-018-0045-5. Epub 2018 Mar 12.

Authors

Elizabeth L Guenther^{1

2

3

4}, Peng Ge⁵, Hamilton Trinh^{1

4

6}, Michael R Sawaya^{1

2

3

4}, Duilio Cascio^{1

2

3

4}, David R Boyer^{1

2

4}, Tamir Gonen^{7

4}, Z Hong Zhou^{3

5

8}, David S Eisenberg^{9

10

11

12}

Affiliations

¹ Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA, USA.
² UCLA-DOE Institute, University of California, Los Angeles, Los Angeles, CA, USA.
³ Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA.
⁴ Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, USA.
⁵ Electron Imaging Center for Nanomachines, California Nano Systems Institute, University of California, Los Angeles, Los Angeles, CA, USA.
⁶ Wayne State University School of Medicine, Detroit, MI, USA.
⁷ Howard Hughes Medical Institute, Janelia Research Campus, Ashburn, VA, USA.
⁸ Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
⁹ Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA, USA. david@mbi.ucla.edu.
¹⁰ UCLA-DOE Institute, University of California, Los Angeles, Los Angeles, CA, USA. david@mbi.ucla.edu.
¹¹ Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA. david@mbi.ucla.edu.
¹² Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, USA. david@mbi.ucla.edu.

Abstract

Proteins in the fibrous amyloid state are a major hallmark of neurodegenerative disease. Understanding the multiple conformations, or polymorphs, of amyloid proteins at the molecular level is a challenge of amyloid research. Here, we detail the wide range of polymorphs formed by a segment of human TAR DNA-binding protein 43 (TDP-43) as a model for the polymorphic capabilities of pathological amyloid aggregation. Using X-ray diffraction, microelectron diffraction (MicroED) and single-particle cryo-EM, we show that the ²⁴⁷DLIIKGISVHI²⁵⁷ segment from the second RNA-recognition motif (RRM2) forms an array of amyloid polymorphs. These associations include seven distinct interfaces displaying five different symmetry classes of steric zippers. Additionally, we find that this segment can adopt three different backbone conformations that contribute to its polymorphic capabilities. The polymorphic nature of this segment illustrates at the molecular level how amyloid proteins can form diverse fibril structures.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Amino Acid Motifs*
Amyloid / chemistry*
Amyloid / genetics*
Amyloidogenic Proteins / chemistry
Cryoelectron Microscopy
Crystallization
DNA-Binding Proteins / chemistry*
DNA-Binding Proteins / genetics*
Humans
Microscopy, Electron, Transmission
Neurodegenerative Diseases / metabolism
Peptides / chemistry
Polymorphism, Genetic*
X-Ray Diffraction

Substances

Amyloid
Amyloidogenic Proteins
DNA-Binding Proteins
Peptides
TARDBP protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding