The nucleus restricts several proteins within and allows others to pass. The restricted proteins possess a nuclear retention sequence or NRS, anchoring them to the nuclear lamins and preventing their transport to the cytosol. The non-restricted proteins, after their synthesis, are transported to their site of action, such as the cytosol or other organelles, with the help of nuclear export signals or NES.
NES are of three types- the canonical 10-residue long leucine-rich signal and other non-canonical NES such as the M9 and KNS signal found in heteronuclear ribonucleoproteins or hnRNPs. Leucine-rich NES is present at the N-terminal end of a polypeptide and is characterized by stretches of leucine and isoleucine residues interspersed with small polar residues. The M9 signal sequence is 38-residues long and present in the C terminal domain of hnRNP A1. M9 signal sequence transports proteins and protein-bound mRNAs bidirectionally across the nucleus in a temperature-sensitive manner. M9 export signal can allow even nuclear-restricted proteins to move to the cytosol at high temperatures and restrict them inside the nucleus at low temperatures. The third non-canonical NES is the 24 amino acid-long KNS signal found in hnRNP K. Like M9, the KNS signal promotes bidirectional nuclear trafficking of proteins and RNA.
Specific nuclear exporters recognize each of these NES. For example, nuclear exporters such as chromosome region maintenance 1 (CRM1), also called exportin 1, recognize and export cargo with leucine-rich signal sequences. During cargo export, Ran-GTP binds to CRM1 to form the CRM1-RanGTP complex. This enables CRM1 and cargo interaction and the formation of a trimeric export complex. The cargo-exporter-RanGTP complex then interacts with the nucleoporins on the cytoplasmic fibrils of the nuclear pore complex or NPC to move across the nucleus. Nup358-RanBP complex on the NPC accelerates Ran GTP to GDP hydrolysis to disassemble the export complex and release the cargo in the cytosol. CRM1 and RanGDP are recycled back to the nucleus for multiple rounds of cargo export.
