Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 1, Pages 197-201Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1320786110
Keywords
protein aggregation; peptide structure; amyotrophic lateral sclerosis
Categories
Funding
- Howard Hughes Medical Institute [P01 NS049134]
- National Institutes of Health [AG029430]
- NIH
- Department of Energy
- Department of Veterans Affairs [1I01BX000506]
- Judith and Jean Pape Adams Charitable Foundation
- NIH [R01 NS39112]
- Direct For Biological Sciences [0958111] Funding Source: National Science Foundation
- Div Of Molecular and Cellular Bioscience [0958111] Funding Source: National Science Foundation
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ALS is a terminal disease of motor neurons that is characterized by accumulation of proteinaceous deposits in affected cells. Pathological deposition of mutated Cu/Zn superoxide dismutase (SOD1) accounts for similar to 20% of the familial ALS (fALS) cases. However, understanding the molecular link between mutation and disease has been difficult, given that more than 140 different SOD1 mutants have been observed in fALS patients. In addition, the molecular origin of sporadic ALS (sALS) is unclear. By dissecting the amino acid sequence of SOD1, we identified four short segments with a high propensity for amyloid fibril formation. We find that fALS mutations in these segments do not reduce their propensity to form fibrils. The atomic structures of two fibril-forming segments from the C terminus, (DSVISLS107)-D-101 and (147)GVIGIAQ(153), reveal tightly packed beta-sheets with steric zipper interfaces characteristic of the amyloid state. Based on these structures, we conclude that both C-terminal segments are likely to form aggregates if available for interaction. Proline substitutions in (DSVISLS107)-D-101 and (147)GVIGIAQ(153) impaired nucleation and fibril growth of full-length protein, confirming that these segments participate in aggregate formation. Our hypothesis is that improper protein maturation and incompletely folded states that render these aggregation-prone segments available for interaction offer a common molecular pathway for sALS and fALS.
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