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Defective nuclear import of Tpr in Progeria reflects the Ran sensitivity of large cargo transport.
- Source :
-
The Journal of cell biology [J Cell Biol] 2013 May 13; Vol. 201 (4), pp. 541-57. Date of Electronic Publication: 2013 May 06. - Publication Year :
- 2013
-
Abstract
- The RanGTPase acts as a master regulator of nucleocytoplasmic transport by controlling assembly and disassembly of nuclear transport complexes. RanGTP is required in the nucleus to release nuclear localization signal (NLS)-containing cargo from import receptors, and, under steady-state conditions, Ran is highly concentrated in the nucleus. We previously showed the nuclear/cytoplasmic Ran distribution is disrupted in Hutchinson-Gilford Progeria syndrome (HGPS) fibroblasts that express the Progerin form of lamin A, causing a major defect in nuclear import of the protein, translocated promoter region (Tpr). In this paper, we show that Tpr import was mediated by the most abundant import receptor, KPNA2, which binds the bipartite NLS in Tpr with nanomolar affinity. Analyses including NLS swapping revealed Progerin did not cause global inhibition of nuclear import. Rather, Progerin inhibited Tpr import because transport of large protein cargoes was sensitive to changes in the Ran nuclear/cytoplasmic distribution that occurred in HGPS. We propose that defective import of large protein complexes with important roles in nuclear function may contribute to disease-associated phenotypes in Progeria.
- Subjects :
- Active Transport, Cell Nucleus
Amino Acid Motifs
Amino Acid Sequence
Fibroblasts metabolism
HeLa Cells
Humans
Lamin Type A
Molecular Sequence Data
Nuclear Localization Signals
Nuclear Pore Complex Proteins genetics
Nuclear Proteins metabolism
Phenotype
Progeria metabolism
Promoter Regions, Genetic
Protein Precursors metabolism
Proto-Oncogene Proteins genetics
alpha Karyopherins genetics
Cell Nucleus metabolism
Nuclear Pore Complex Proteins metabolism
Progeria genetics
Proto-Oncogene Proteins metabolism
alpha Karyopherins metabolism
ran GTP-Binding Protein metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1540-8140
- Volume :
- 201
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- The Journal of cell biology
- Publication Type :
- Academic Journal
- Accession number :
- 23649804
- Full Text :
- https://doi.org/10.1083/jcb.201212117