Nuclear Localization Signals and Import

Proteins targeted to the nucleus carry short stretches of amino acid sequences called the nuclear localization signal or NLS. Classical nuclear localization signals are of two types: monopartite and bipartite NLS. Monopartite classical NLS (cNLS) consists of a single cluster of 4-8 amino acids. Bipartite cNLS consists of two clusters of 2-3 amino acids and a 9-12 residue long proline-rich linker bridging the two clusters. Signal clusters are rich in positively charged amino acids such as lysine and arginine and are present as loops or signal patches. In addition to cNLS, other classes of NLS include:
1) Non-classical NLS,
2) Putative NLS,
3) Spatial epitope NLS,
4) Cryptic NLS, and
5) Multiple NLS.

NLS is recognized by soluble nuclear import receptors called importins that are made of alpha and beta subunits. Importin alpha binds cargo proteins to form a receptor-cargo complex. Importin beta interacts with FG nucleoporins and shuttles the receptor-cargo complex across the nucleus. Once inside the nucleus, importin beta interacts with the GTP-bound small monomeric Ran GTPase, which leads to dissociation of the importin alpha-cargo complex. Cas-Ran GTP, the export receptor for importin alpha, associates with Nup 50 and importin alpha to release the cargo into the nucleus. Importin beta-Ran GTP complex and CAS-Ran GTP-Importin alpha complex shuttles back to the cytosol for another round of nuclear import.