Structures of importins.

Abstract

Importins are nuclear transport receptors of the karyopherin superfamily. They recognize nuclear proteins that are synthesized in the cytoplasm and translocate them to the nucleus (Mattaj and Englmeier 1998; Weis 1998; Gorlich and Kutay 1999; Nakielny and Dreyfuss 1999). Macromolecules are targeted to the nucleus by a signal sequence that mediates the interaction with an importin. The founding member of the karyopherin superfamily is the importin-αβ heterodimer, which binds and transports proteins containing classical, positively-charged nuclear localization signals. The α component of the heterodimer (known in the literature as importin-α, karyopherin-α, hSRP1 or p58) functions as an adapter by binding the nuclear localization signal (NLS)-containing protein and the carrier component β (Fig. 1). The β-component (importin-β, karyopherin-β1, p97) docks the complex to distinct sites along the fibrils of the nuclear pore complex (NPC). At the nucleoplasmic side, β releases its cargo by interacting with the small GTPase Ran in its GTPbound form. The NLS-containing protein diffuses within the nucleus to exert its function, while the soluble components of the transport machinery are recycled back to the cytoplasm for a new import cycle. The β-RanGTP complex can exit the nucleus directly, while the adapter a requires a specific exportin of the karyopherin-β superfamily to be translocated out the nucleus. At the cytoplasmic side, the GTPase loses its high affinity for β as it is hydrolyzed to the GDP-bound form by the combined action of a RanBD (Ran binding domain) and RanGAP (see Chap. 3 by Bischoff and references therein). RanGDP is transported back into the nucleus via an association with the transport factor NTF2, and there converted to the GTP-bound form by the action of a specific GEF (the nuclear guanine nucleotide exchange factor RCC1). The asymmetric distribution of cytoplasmic RanGDP and nuclear RanGTP drives the directionality of transport processes, ensuring cargo loading and cargo release in the appropriate cell compartments.