CRM1-mediated recycling of snurportin 1 to the cytoplasm

Importin beta is a major mediator of import into the cell nucleus. Importin beta binds cargo molecules either directly or via two types of adapter mol ecules, importin alpha, for import of proteins with a classical nuclear loc alization signal (NLS), or snurportin 1, for import of m(3)G-capped U snRNP s. Both adapters have an NH2-terminal importin beta-binding domain for bind ing to, and import by, importin beta, and both need to be returned to the c ytoplasm after having delivered their cargoes to the nucleus. We have shown previously that CAS mediates export of importin alpha. Here we show that s nurportin 1 is exported by CRM1, the receptor for leucine-rich nuclear expo rt signals (NESs). However, the interaction of CRM1 with snurportin 1 diffe rs from that with previously characterized NESs, First, CRM1 binds snurport in 1 50-fold stronger than the Rev protein and 5,000-fold stronger than the minimum Rev activation domain. Second, snurportin 1 interacts with CRM1 no t through a short peptide but rather via a large domain that allows regulat ion of affinity. Strikingly, snurportin 1 has a low affinity for CRM1 when bound to its m(3)G-capped import substrate, and a high affinity when substr ate-free. This mechanism appears crucial for productive import cycles as it can ensure that CRM1 only exports snurportin 1 that has already released i ts import substrate in the nucleus.