Atomic Structures of Segments from TDP-43 LCD and insight into Reversible and Pathogenic Aggregation

Details

• Alternative Title:
  Nat Struct Mol Biol
• Personal Author:
  Guenther, Elizabeth L. ; Cao, Qin ; Trinh, Hamilton ; Lu, Jiahui ; Sawaya, Michael R. ; Cascio, Duilio ; Boyer, David R. ; Rodriguez, Jose A. ; Hughes, Michael P. ; Eisenberg, David S.
• Description:
  The normally soluble TAR DNA-binding protein 43 (TDP-43) is found aggregated both in reversible stress granules and in irreversible pathogenic amyloid. In TDP-43, the low-complexity domain (LCD) is believed to be involved in both types of aggregation. To uncover the structural origins of these two modes of β-sheet-rich aggregation, we have determined ten structures of segments of the LCD of human TDP-43. Six of these segments form steric zippers characteristic of the spines of pathogenic amyloid fibrils; four others form LARKS, the labile amyloid-like interactions characteristic of protein hydrogels and proteins found in membraneless organelles, including stress granules. Supporting a hypothetical pathway from reversible to irreversible amyloid aggregation, we found that familial ALS variants of TDP-43 convert LARKS to irreversible aggregates. Our structures suggest how TDP-43 adopts both reversible and irreversible β-sheet aggregates and the role of mutation in the possible transition of reversible to irreversible pathogenic aggregation.
• Subjects:
  Amyotrophic Lateral Sclerosis Article DNA-Binding Proteins Humans Mutation Organelles Protein Conformation, Beta-Strand
• Source:
  Nat Struct Mol Biol. 25(6):463-471
• Pubmed ID:
  29786080
• Pubmed Central ID:
  PMC5990464
• Document Type:
  Journal Article
• Funding:
  R01 AG029430/NIA NIH HHS/National Institute on Aging/United States ; P41 GM103403/NIGMS NIH HHS/National Institute of General Medical Sciences/United States ; RF1 AG054022/NIA NIH HHS/National Institute on Aging/United States ; S10 OD021527/ODCDC CDC HHS/Office of the Director/United States ; Howard Hughes Medical Institute/United States ; U24 GM116792/NIGMS NIH HHS/National Institute of General Medical Sciences/United States ; S10 RR023057/NCRR NIH HHS/National Center for Research Resources/United States
• Volume:
  25
• Issue:
  6
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:0836ffeb040acacf057bd72e891c1a81d905a301c3c750ab0946b2bcb7a268c3
• Download URL:
  https://stacks.cdc.gov/view/cdc/80352/cdc_80352_DS1.pdf
• File Type:
  [PDF - 2.97 MB ]