Journal
CELL
Volume 155, Issue 3, Pages 582-593Publisher
CELL PRESS
DOI: 10.1016/j.cell.2013.09.023
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Funding
- National Cancer Institute Cancer Center [P30 CA068485]
- NIH [R37GM051219, F31NS070431, 1DP2OD004483, T32CA119925, T32GM008320]
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The conserved multifunctional protein Gle1 regulates gene expression at multiple steps: nuclear mRNA export, translation initiation, and translation termination. A GLE1 mutation (FinMajor) is causally linked to human lethal congenital contracture syndrome-1 (LCCS1); however, the resulting perturbations on Gle1 molecular function were unknown. FinMajor results in a proline-phenylalanine-glutamine peptide insertion within the uncharacterized Gle1 coiled-coil domain. Here, we find that Gle1 self-associates both in vitro and in living cells via the coiled-coil domain. Electron microscopy reveals that highmolecular- mass Gle1 oligomers form similar to 26 nm diameter disk-shaped particles. With the Gle1-Fin(Major) protein, these particles are malformed. Moreover, functional assays document a specific requirement for proper Gle1 oligomerization during mRNA export, but not for Gle1's roles in translation. These results identify a mechanistic step in Gle1's mRNA export function at nuclear pore complexes and directly implicate altered export in LCCS1 disease pathology.
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