Multiple roads between the nucleus and the cytoplasm: classes of linear NLSs and NESs and their receptors

Nucleocytoplasmic transport relies on targeting signals within cargo polypeptides, typically as short linear motifs but sometimes as folded domains. These signals are recognized by the Karyopherin-β (Kap) family of importins, exportins, and biportins. Despite the number of Kaps, only a few linear signal classes are well-defined: the classical nuclear localization signal (cNLS) recognized by importin-α (IMPα), which in turn binds IMPβ to form the IMPα/β heterodimer, the IMPβ-binding domain, the Pro-Tyr NLS of transportin-1 (TNPO1/Kapβ2), the IK-NLS of Kap121/importin-5, and the RS/E- and RSY-NLSs of TNPO3, along with the classical nuclear export signal (NES) of exportin-1 (XPO1/CRM1) and the phosphorylated NES of yeast Msn5. This review summarizes recent structural and biochemical advances that define these signals and their recognition rules and highlights the remaining gaps in our understanding of linear signals across the Kap family.