XGle1 functions during mRNA export in an oligomeric complex that is altered in human disease

Andrew W. Folkmann; Scott E. Collier; Xiaoyan Zhan; Melanie D. Ohi; Susan R. Wente

doi:10.1016/j.cell.2013.09.023

XGle1 functions during mRNA export in an oligomeric complex that is altered in human disease

Andrew W. Folkmann, Scott E. Collier, Xiaoyan Zhan, Aditi, Melanie D. Ohi, Susan R. Wente

Research output: Contribution to journal › Article › peer-review

Abstract

The conserved multifunctional protein Gle1 regulates gene expression at multiple steps: nuclear mRNA export, translation initiation, and translation termination. A GLE1 mutation (Fin_Major) is causally linked to human lethal congenital contracture syndrome-1 (LCCS1); however, the resulting perturbations on Gle1 molecular function were unknown. Fin_Major 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-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.

Original language	English (US)
Pages (from-to)	582
Number of pages	1
Journal	Cell
Volume	155
Issue number	3
DOIs	https://doi.org/10.1016/j.cell.2013.09.023
State	Published - Oct 24 2013
Externally published	Yes

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2013.09.023

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title = "XGle1 functions during mRNA export in an oligomeric complex that is altered in human disease",

abstract = "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.",

author = "Folkmann, {Andrew W.} and Collier, {Scott E.} and Xiaoyan Zhan and Aditi and Ohi, {Melanie D.} and Wente, {Susan R.}",

note = "Funding Information: The authors thank T.R. Dawson for advice and critical reading of the manuscript; the Wente laboratory, M. Rout, and C. Cole for discussions; C. Cole for yeast strains; and Y. Takizawa for technical assistance with cryo-EM. This work was supported in part by the National Cancer Institute Cancer Center Support Grant P30 CA068485 utilizing the Cell Imaging Shared Resource and grants NIH R37GM051219 (to S.R.W.), NIH F31NS070431 (to A.W.F.), NIH 1DP2OD004483 (to M.D.O.) and training positions on T32CA119925 (to A.W.F.) and T32GM008320 (to S.E.C.). ",

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AU - Folkmann, Andrew W.

AU - Collier, Scott E.

AU - Zhan, Xiaoyan

AU - Aditi,

AU - Ohi, Melanie D.

AU - Wente, Susan R.

N1 - Funding Information: The authors thank T.R. Dawson for advice and critical reading of the manuscript; the Wente laboratory, M. Rout, and C. Cole for discussions; C. Cole for yeast strains; and Y. Takizawa for technical assistance with cryo-EM. This work was supported in part by the National Cancer Institute Cancer Center Support Grant P30 CA068485 utilizing the Cell Imaging Shared Resource and grants NIH R37GM051219 (to S.R.W.), NIH F31NS070431 (to A.W.F.), NIH 1DP2OD004483 (to M.D.O.) and training positions on T32CA119925 (to A.W.F.) and T32GM008320 (to S.E.C.).

PY - 2013/10/24

Y1 - 2013/10/24

N2 - 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.

AB - 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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XGle1 functions during mRNA export in an oligomeric complex that is altered in human disease

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