Structural Determinants and Mechanism of Mammalian CRM1 Allostery
Proteins carrying nuclear export signals cooperatively assemble with the export factor CRM1 and the effector protein RanGTP. In lower eukaryotes, this cooperativity is coupled to CRM1 conformational changes; however, it is unknown if mammalian CRM1 maintains its compact conformation or shows similar...
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Veröffentlicht in: | Structure (London) 2013-08, Vol.21 (8), p.1350-1360 |
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Sprache: | eng |
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Zusammenfassung: | Proteins carrying nuclear export signals cooperatively assemble with the export factor CRM1 and the effector protein RanGTP. In lower eukaryotes, this cooperativity is coupled to CRM1 conformational changes; however, it is unknown if mammalian CRM1 maintains its compact conformation or shows similar structural flexibility. Here, combinations of small-angle X-ray solution scattering and electron microscopy experiments with molecular dynamics simulations reveal pronounced conformational flexibility in mammalian CRM1 and demonstrate that RanGTP binding induces association of its N- and C-terminal regions to form a toroid structure. The CRM1 toroid is stabilized mainly by local interactions between the terminal regions, rather than by global strain. The CRM1 acidic loop is key in transmitting the effect of this RanGTP-induced global conformational change to the NES-binding cleft by shifting its population to the open state, which displays enhanced cargo affinity. Cooperative CRM1 export complex assembly thus constitutes a highly dynamic process, encompassing an intricate interplay of global and local structural changes.
•Hybrid methods show mammalian CRM1 as highly flexible•Free human CRM1 exists in extended superhelical and compact toroidal states•RanGTP binding to CRM1 reduces CRM flexibility by shifting it to compact forms•Acidic loop modulates the open-to-closed nuclear export signal cargo-binding cleft
Using hybrid methods, Dölker et al. reveal the high flexibility of mammalian exportin CRM1 behind an intriguing coupling between overall conformation and local positional changes. The rearrangements mediate cooperativity between the RanGTP- and the cargo-binding sites, resulting in remarkable long distance coupling. |
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ISSN: | 0969-2126 1878-4186 |
DOI: | 10.1016/j.str.2013.05.015 |