PROSITE documentation PDOC50177

Nuclear transport factor 2 domain profile

Nucleocytoplasmic transport is mediated by large supramolecular structures that span the nuclear envelope called nuclear pore complexes (NPC). Classical import pathway involves proteins containing nuclear localisation signal (NLS). This transport signal is recognized in the cytosol by importin α. Binding of the resulting complex to the cytoplasmic fibrils of the NPC is mediated by the cytosolic factor importin β. From their, the substrate-α-β transport complex move to a central NPC region, where it pass through a gated channel [1,2].

This nuclear import as well as the export pathway are dependent on the GTPase cycle of Ran protein, a Ras-related GTPase. RanGDP is generated in the cytoplasm by RanGTPase-activating protein and Ran is recharged with GTP in the nucleus by the RCC1 factor (see <PDOC00544>). RanGTP is exported from the nucleus bound to importin proteins and must be recycled back to the nucleus for new exchange. This recycling step of Ran is mediated by Nuclear transport factor 2 (NTF2) [3,4]. This small protein specifically binds to RanGDP and the nuclear pore proteins containing phenylalanine-glycine (XFXFG) repeats [5,6]. These interactions are required for the transport of RanGDP into the nucleus [6].

Structurally [7], NTF2 forms an α-β barrel that opens at one end to form a distinctive hydrophobic cavity. The crystal structure of NTF2 in complex with RanGDP [8] shows that the interaction is mediated by the hydrophobic cavity of NTF2 and the putative switch II loop of Ran. The contribution of the switch II loop certainly accounts for the ability of NTF2 to discriminate between GDP and GTP-bound forms of Ran.

The following proteins contain a region similar to NTF2:

• Eukaryotic NXF proteins [9]. These are nuclear mRNA export factors. These proteins contain, in addition to a NTF2 domain, a number of leucine-rich repeats and a UBA domain.
• Eukaryotic NXT1/NXT2 proteins [9]. These proteins are stimulators of protein export for NES-containing proteins. The also play a role in mRNA nuclear export. They heterodimerize with NFX proteins. In contrast to NTF2, NXT1 and NXT2 preferentially bind RanGTP.
• eukaryotic Ras-GTPase-activating protein (GAP)-binding proteins (G3BP's). These proteins contain one NTF2 domain and one RRM (see <PDOC00030>).

We developed a profile for NTF2 that spans the complete domain.