细胞期刊(Cell)2013-10-28 8:46 PM

Gle1 Functions during mRNA Export in an Oligomeric Complex that Is Altered in Human Disease

Highlights
- Gle1 self-associates via its conserved, essential coiled-coil domain
- Oligomerization of Gle1 is required for mRNA export and not translation
- Gle1 oligomers form disk structures that are perturbed in the LCCS1 disease variant
- mRNA export dysregulation at nuclear pore complexes is linked to LCCS1 pathology
Summary
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 high-molecular-mass Gle1 oligomers form ∼26 nm diameter disk-shaped particles. With the Gle1-FinMajor 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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细胞期刊(Cell)

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