Gle1 functions during mRNA export in an oligomeric complex that is altered in human disease.
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.
Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Andrew W
AW
Folkmann
Scott E
SE
Collier
Xiaoyan
X
Zhan
Aditi
Melanie D
MD
Ohi
Susan R
SR
Wente
D021581:Active Transport, Cell Nucleus; D001176:Arthrogryposis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006367:HeLa Cells; D006801:Humans; D009154:Mutation; D022022:Nuclear Pore / Q000378:metabolism; D029543:Nucleocytoplasmic Transport Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000378:metabolism
C474082:Gle1 protein, human; D029543:Nucleocytoplasmic Transport Proteins; D012333:RNA, Messenger