Chromosome region maintenance 1/exportin1/Xpo1 (CRM1) associates with the GTPase Ran to mediate the nuclear export of proteins bearing a leucine-rich nuclear export signal (NES). CRM1 consists of helical hairpin HEAT repeats and a C-terminal helical extension (C-extension) that inhibits the binding of NES-bearing cargos. We report the crystal structure and small-angle X-ray scattering analysis of a human CRM1 mutant with enhanced NES-binding activity due to deletion of the C-extension. We show that loss of the C-extension leads to a repositioning of CRM1's C-terminal repeats and to a more extended overall conformation. Normal mode analysis predicts reduced rigidity for the deletion mutant, consistent with an observed decrease in thermal stability. Point mutations that destabilize the C-extension shift CRM1 to the more extended conformation, reduce thermal stability, and enhance NES-binding activity. These findings suggest that an important mechanism by which the C-extension regulates CRM1's cargo-binding affinity is by modulating the conformation and flexibility of its HEAT repeats.

dx.doi.org/10.1016/j.str.2013.06.003, hdl.handle.net/1765/40751
Structure
Erasmus MC: University Medical Center Rotterdam

Dian, C, Bernaudat, F, Langer, K, Oliva, O.M.F, Fornerod, M.W.J, Schoehn, G, … Petosa, C. (2013). Structure of a Truncation Mutant of the Nuclear Export Factor CRM1 Provides Insights into the Auto-Inhibitory Role of Its C-Terminal Helix. Structure, 21(8), 1338–1349. doi:10.1016/j.str.2013.06.003