Protein import, nucleus importins

Proteins similar to importins, referred to as ex-portins, are involved in export of many macromolecules from the nucleus. Cargo molecules for export carry nuclear export signals (NESs). Ran proteins are involved in this process also, and it is now established that the processes of import and export share a number of common feamres. 

Importins are transport proteins at the nuclear pore complex, needed for the selective import of proteins into the nucleus. They recognize nuclear localization signal sequences of cargo proteins. 

Sequence of amino acids that determine the transport of proteins into the nucleus. Although there is no clear consensus, nuclear localization signals tend to be rich in positively charged residues, which allow interaction with proteins from the nuclear import machinery (i.e., importins). 

Nuclear importation is mediated by a number of proteins that cycle between the cytosol and the nucleus (Fig. 27-37), including importin a and J8 and a small GTPase known as Ran. A heterodimer of importin a and J8 functions as a soluble receptor for proteins targeted to the nucleus, with the a subunit binding NLS-bearing... 

Figure 12.2 Model for importin-mediated nuclear import and export. NLS-containing proteins in the cytoplasm bind to importin family members in the cytoplasm and are translocated through the NPC. Once inside the nucleus, Ran-GTP interacts with the importin-cargo complex to facilitate complex dissociation. Similarly, proteins to be exported from the nucleus interact with one of the exportins, but in contrast to the case with importins, assembly of this complex is promoted by Ran-GTP. As the complex, presumably with Ran-GTP bound, enters the cytoplasm, the GTP is hydrolyzed to GDP, which induces the release of the cargo from exportin.

Fig. 10.8 Above, import of the transcription factor NF-AT4 into the nucleus. In activated cells, import is initiated by calcineurin-mediated dephosphorylation of NF-AT4. Dephosphorylation unmasks the nuclear-localization signal (NLS), and at the same time blocks the nuclear export signal (NES). The NES is recognized by the exportin protein (Crml). Nuclear export is an active process. Moreover, nuclear export requires rephosphorylation of the NF-AT4 transcription factor. It is indicated that dephosphorylation by calcineurin and nuclear export are mutually exclusive, because calcineurin and Crm 1 compete for a common binding site on NES. When NES binds to Crml, NT-AT4 is exported from the nucleus, and when calcineurin binds to NES, NF-AT4 remains in the nucleus and forms a transcriptionally active complex. Below, how the extent of dephosphorylation controls the transcriptional activity of NF-AT4. When NF-AT4 is fully phosphorylated, NLS is hidden and the transcription factor remains in the cytoplasm. When NF-AT4 is only partially dephosphorylated, NLS is exposed and can interact with importin a/b which promote nuclear import, and at the same time, NES can interact with the exportin Crml, which promotes nuclear export. The consequence is that the transcription factor shuttles between the nucleus and the cytoplasm and is not transcriptionally active. In order to become transcriptionally fully active, NF-AT4 must be completely dephosphorylated. This prevents export from the nucleus by blocking NES, and may increase the affinity of the transcription factor for DNA by exposure of its trans-activating domain (TAD). (The entire scheme is reproduced with permission of Drs Patrick G. Hogan and Anjana Rao and Nature from Fig. 1 in ref. 68.)...

Fig. 10.22. Nuclear import. Proteins with the nuclear localization signal bind to importins, which carry them through the nuclear pore into the nucleus. The monomeric G protein Ran containing bound GTP binds to one of the subunits of importin. This causes dissociation of the importin subunits and release of the imported protein in the nucleus. The Ran-importin complex exits a nuclear pore. On the cytoplasmic side, a RanGAP (GTPase activating protein) activates the hydrolysis of GTP to GDP, which causes dissociation of the complex. RanGDP is subsequently returned to the nucleus, where an accessory protein activates dissociation of GDP and association of GTP.

Importins A class of proteins involved in importing molecules into the nucleus. 

---