Figure 2.

Nucleocytoplasmic transport and chaperone function of karyopherins. Left: Schematic diagram showing the RanGTP/GDP cycle through the nuclear pore complex. In the cytoplasm, RanGAP1, together with RanBP, hydrolyses RanGTP to maintain high cytoplasmic concentrations of RanGDP. In the nucleus, RCC1 (nuclear RanGEF) facilitates GTP-GDP exchange, causing high concentrations of RanGTP. These regulators maintain higher concentrations of RanGDP in the cytoplasm whilst preserving high levels of RanGTP in the karyoplasm, leading to a gradient required for energy-dependent nucleocytoplasmic transport. Right: Schematic diagram of the classical nuclear import and export pathway. During nuclear import, KPNB1 binds to KPNA, which itself is bound to the classical NLS (cNLS) of cargo, forming a trimeric complex. KPNA also exerts chaperone function to cargo-cNLS by shielding basic residues from hydrophobic/ionic interactions, which maintains a cargo protein in its native soluble state. KPNB1 carries the complex through the nuclear pore complex, where RanGTP binds, causing a conformational change in the bound importin (note, some KPNBs shown as beta bind directly to cargo forming a dimeric complex which directly translocates to the nucleus). This results in a trimeric complex of KPNA, nuclear export factor CAS, and RanGTP, and a dimeric complex consisting of KPNB1 and RanGTP. Both complexes then translocate back to the cytoplasm where their respective RanGTPs are hydrolysed to bind to the next cargo. During export, Exportin/KPNB (beta) bound to RanGTP binds to the cargo-NES of the cargo in the nucleoplasm. This complex is exported through the nuclear pore complex into the cytoplasm where RanGTP is hydrolysed, which triggers cargo release. CAS = cellular apoptosis susceptibility protein; RAN = Ras-related nuclear; RCC1 = regulator of chromosome condensation 1; Ran-GAP = Ran GTPase activating protein; RanBP1 = Ran binding protein 1; RanGEF = Ran guanine exchange factor.