Nuclear export signal

A nuclear export signal (NES) is a short amino acid sequence of 4 hydrophobic residues in a protein that targets it for export from the cell nucleus to the cytoplasm through the nuclear pore complex using nuclear transport. It has the opposite effect of a nuclear localization signal, which targets a protein located in the cytoplasm for import to the nucleus. The NES is recognized and bound by exportins. In silico analysis of known NESs found the most common spacing of the hydrophobic residues to be L_xxxL_xxL_xL, where "L" is a hydrophobic residue (often leucine) and "x" is any other amino acid; the spacing of these hydrophobic residues may be explained by examination of known structures that contain an NES, as the critical residues usually lie in the same face of adjacent secondary structures within a protein, which allows them to interact with the exportin.Ribonucleic acid (RNA) is composed of nucleotides, and thus, lacks the nuclear export signal to move out of the nucleus. As a result, most forms of RNA will bind to a protein molecule to form a ribonucleoprotein complex to be exported from the nucleus.

Nuclear export first begins with the binding of Ran-GTP (a G-protein) to exportin. This causes a shape change in exportin, increasing its affinity for the export cargo. Once the cargo is bound, the Ran-exportin-cargo complex moves out of the nucleus through the nuclear pore. GTPase activating proteins (GAPs) then hydrolyze the Ran-GTP to Ran-GDP, and this causes a shape change and subsequent exportin release. Once no longer bound to Ran, the exportin molecule loses affinity for the nuclear cargo as well, and the complex falls apart. Exportin and Ran-GDP are recycled to the nucleus separately, and guanine exchange factor (GEF) in the nucleus switches the GDP for GTP on Ran.

NES signal was first discovered in the human immunodeficiency virus type 1 (HIV-1) Rev protein and cAMP-dependent protein kinase inhibitor (PKI). The karyopherin receptor CRM1 has been identified as the export receptor for leucine-rich NESs in several organisms and is an evolutionary conserved protein. The export mediated by CRM1 can be effectively inhibited by the fungicide leptomycin B (LMB), providing excellent experimental verification of this pathway.

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