Structural Determinants Of Conformational Flexibility And Long-Range Allostery Of The Crm1 Export Complex

In eukaryotes the nucleocytoplasmic transport of macromolecules is mainly mediated by soluble nuclear transport receptors of the karyopherin-β superfamily termed importins and exportins. The prototypical and highly versatile exportin CRM1 (chromosome region maintenance 1) is essential for nuclear depletion of numerous structurally and functionally unrelated protein and RNP cargoes. CRM1 has been shown to bind RanGTP (GTP bound RAs-related nuclear protein) and cargo proteins in an allosteric manner and to adopt a toroidal structure in several functional transport complexes. It was thought to maintain this conformation, with N- and C-terminal regions in close proximity, throughout the entire nucleocytoplasmic transport cycle. A recently solved structure of cargo-free CRM1 however revealed a superhelical, open conformation. Using molecular dynamics simulations, two distinct features of this conformation and their influence on the structural stability were investigated. One of those, the C-terminal helix, was identified as a major stabilising factor of the superhelical conformation. We furthermore showed that the overall configuration of CRM1 influences the local configuration of the cargo binding site. Based on these results we suggest a mechanism for the observed cooperative binding.