Atomic-level evidence for packing and positional amyloid polymorphism by segment from TDP-43 RRM2
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 T...
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Published in | Nature structural & molecular biology Vol. 25; no. 4; pp. 311 - 319 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Nature Publishing Group
01.04.2018
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Subjects | |
Online Access | Get full text |
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Summary: | 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
DLIIKGISVHI
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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 P41 GM103403; NSF MCB 1616265; GM071940; 1S10RR23057; 1U24GM116792; DBI-1338135 National Science Foundation (NSF) National Inst. of Health Present address: Wayne State University School of Medicine, Detroit, MI, USA. Correspondence and requests for materials should be addressed to D.S.E. Present address: Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, USA. |
ISSN: | 1545-9993 1545-9985 |
DOI: | 10.1038/s41594-018-0045-5 |