A nuclear localizing sequence (NLS) is an amino acid sequence which acts like a 'tag' on the exposed surface of a protein. This sequence is used to target the protein to the cell nucleus through the Nuclear Pore Complex and to direct a newly synthesized protein into the nucleus via its recognition by cytosolic nuclear transport receptors. Typically, this signal consists of one or more short sequences of positively charged lysines or arginines. Different nuclear localized proteins may share the same NLS. An NLS has the opposite function of a nuclear export signal, which targets proteins out of the nucleus.

Types of nuclear localization signals

The first NLS to be discovered is the sequence PKKKRKV in SV40 large T antigen ^[1] . The NLS of nucleoplasmin, KR[PAATKKAGQA]KKKK, is the prototype of ubiquitous bipartite signal: two clusters of basic amino acids, separated by a spacer of about 10 amino acids http://www.jcb.org/cgi/external_ref?access_num=3417784&link_type=PUBMED. Both signals are recognized by importin ?. Importin ? contains a bipartite NLS itself, which is specifically recognized by importin ?. The latter can be considered the actual import mediator.

Chelsky et al. proposed the consensus sequence K-K/R-X-K/R for monopartite NLSs http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=2668735. A Chelsky sequence may, therefore, be part of the downstream basic cluster of a bipartite NLS. Makkerh et al http://www.current-biology.com/content/article/abstract?uid=PIIS0960982202006486 carried out comparative mutagenesis on the nuclear localisation signals of SV40 T-Antigen (monopartite), C-myc (monopartite) and nucleoplasmin (bipartite), and showed amino acid features common to all three. Notably the role of neutral and acidic amino acids was shown for the first time in contributing to the efficiency of the NLS ^[2] .

There are many other types of NLS, such as the acidic M9 domain of hnRNP A1, the sequence KIPIK in yeast transcription repressor Mat?2, and the complex signals of U snRNPs. Most of these NLSs appear to be recognized directly by specific receptors of the importin ? family without the intervention of an importin ?-like protein http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=9759490&ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum.

A signal that appears to be specific for the massively produced and transported ribosomal proteins http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T36-3WP2JNF-1J&_user=10&_coverDate=06%2F11%2F1999&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=2800999c993fd610f3e2c90766d2ce3f,http://estore.asm.org/viewItemDetails.asp?ItemID=277, seems to come with a specialized set of importin ?-like nuclear import receptors http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-418PWY3-8&_user=10&_coverDate=05%2F30%2F1997&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=a6e2d9da7b827ac7424962c70b0f2de7.

Mechanism of nuclear import

Proteins gain entry into the nucleus through the nuclear envelope. The nuclear envelope consist of concentric membranes, the outer and the inner membrane. These are the gateways to the nucleus. The envelope consist of pores or large nuclear complexes.

A protein translated with a NLS will bind strongly to importin (aka karyopherin), and together, the complex will move through the nuclear pore. At this point, Ran-GTP will bind to the importin-protein complex, and its binding will cause the importin to lose affinity for the protein. The protein is released, and now the Ran-GTP/importin complex will move back out of the nucleus through the nuclear pore. A GTPase activating protein (GAP) in the cytoplasm hydrolyzes the Ran-GTP to GDP, and this causes a conformational change in Ran, ultimately reducing its affinity for importin. Importin is released and Ran-GDP is recycled back to the nucleus where guanine exchange factor (GEF) exchanges its GDP back for GTP.

Nuclear export

Exporting proteins out of the nucleus is programmed by a nuclear export signal.

References

Additional Reading

Gorlich, D. (1997). Nuclear protein import. Current Opinion in Cell Biology, 9(3), 412-419.
C. Patrick Lusk, Gunter Blobel, and Megan C. King (2007). Highway to the inner nuclear membrane: rules for the road. Nature Reviews Molecular Cell Biology 8, 414-420 (May 2007).

de:Kernlokalisierungssignal fr:Signal de localisation nucléaire pt:Sinal de localização nuclear