期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 114, 期 7, 页码 E1111-E1117出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1620293114
关键词
C9orf72 repeat expansion; PRn poly-dipeptide; nuclear pore; FG domain; labile cross-beta polymers
资金
- National Institutes of Health [U01 GM10762301, R01 GM33397]
The toxic proline: arginine (PRn) poly-dipeptide encoded by the (GGGGCC) (n) repeat expansion in the C9orf72 form of heritable amyotrophic lateral sclerosis (ALS) binds to the central channel of the nuclear pore and inhibits the movement of macromolecules into and out of the nucleus. The PRn poly-dipeptide binds to polymeric forms of the phenylalanine: glycine (FG) repeat domain, which is shared by several proteins of the nuclear pore complex, including those in the central channel. A method of chemical foot-printing was used to characterize labile, cross-beta polymers formed from the FG domain of the Nup54 protein. Mutations within the footprinted region of Nup54 polymers blocked both polymerization and binding by the PRn poly-dipeptide. The aliphatic alcohol 1,6-hexanediol melted FG domain polymers in vitro and reversed PRn-mediated enhancement of the nuclear pore permeability barrier. These data suggest that toxicity of the PRn poly-dipeptide results in part from its ability to lock the FG repeats of nuclear pore proteins in the polymerized state. Our study offers a mechanistic interpretation of PRn poly-dipeptide toxicity in the context of a prominent form of ALS.
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