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Progerin guilty of size discrimination

The Journal of Cell Biology
The Rockefeller University Press
Publication Date
DOI: 10.1083/jcb.2014iti1
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JCB_2014iti.indd In This Issue JCB • VOLUME 201 • NUMBER 4 • 2013490 Text by Mitch Leslie [email protected] Progerin guilty of size discrimination A mutant protein respon- sible for Hutchinson- Gilford Progeria syn- drome (HGPS) bars large pro- teins from entering the nucleus, Snow et al. reveal. The culprit in HGPS, a fatal disease that resembles pre- mature aging, is Progerin. This defective version of the lamin A protein impairs cells in many ways, including reducing nuclear levels of the RanGTPase. Ran is crucial for nuclear import and export, as it stimulates unloading of cargo that has just entered the nucleus and loading of cargo that’s ready to exit. Progerin also impedes the import of Tpr, which forms the basket-like structure on the inner side of nu- clear pores. But the mechanism behind this exclusion wasn’t clear. One possibility is that Progerin disrupts the activity of Tpr’s nuclear localization sequence (NLS). To test this idea, Snow et al. replaced Tpr’s NLS with the localization sequence from the SV40 virus T antigen, a protein that readily enters the nucleus. The modifi ed Tpr was still locked out, however, suggesting that the effect wasn’t related to its NLS. Tpr forms a dimer that weighs in at 535 kD, making it one of the largest proteins to traverse nuclear pores. Snow et al. found that Progerin limits the nuclear import of three other hefty proteins— Tip60, p400, and Orc2. This size effect stems from the reduction in nuclear Ran levels triggered by Progerin. For reasons that are still unclear, large cargoes require more Ran to enter the nucleus. These fi ndings suggest that some cellular defects of HGPS might result from the exclusion of large cargoes, such as multisubunit enzyme complexes, from the nucleus. Snow, C.J., et al. 2013. J. Cell Biol. Why metaphase chromosomes wander C ivelekoglu-Scholey et al. ex- plain why some metaphase chromosomes shift positions. After chrom

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