| Accession: | |
|---|---|
| Functional site class: | NES Nuclear Export Signals |
| Functional site description: | The Nuclear Export Signal (NES) is a linear motif involved in the regulated export of macromolecules from the nucleus via the nuclear pores. Import and export of macromolecules is the main way to communicate between cytosol and nucleus. Therefore, although many nuclear proteins do not need to be re-exported, a substantial number of nuclear proteins can shuttle between the nucleus and cytoplasm. In such proteins, the accessibility of the import and export signals needs to be regulated, or they will immediately be returned to the other compartment. Thus, open and closed conformations of NES-bearing proteins are likely to be common features. The nuclear exporter protein, CRM1 mediates the nuclear export of cargo proteins by recognizing amphipathic NESes. These bind in a number of permutations including forward and reverse orientations. Mutations in the NES motif or their recognition regions can lead to several pathological conditions in the cell, including cancer. |
| ELMs with same func. site: | TRG_NES_CRM1_1 TRG_NESrev_CRM1_2 |
| ELM Description: | Accessible peptides matching the leucine-rich nuclear export signal (NES) motif bind to the CRM1 exportin protein. Since the NES has been reported as four to five conserved hydrophobic residues, it has presented a particular problem for experimental verification. Solving 3D structures of putative NES motif-bearing proteins has often revealed that the apparent export signals are buried in the hydrophobic core of globular domains where they cannot function as linear motifs (Gibson,2013). While some of the reported NES peptides are therefore unlikely to be true, many proteins do return to the cytoplasm from the nucleus by this mechanism. The NES pattern in ELM was therefore derived exclusively from reported instances that were not buried in domain cores. The conserved motif is found to be longer and less hydrophobic than originally reported, with a negatively charged residue at each end. An educational structure to view is the MapKapK2 kinase (1KWP), where the NES is conditionally packed onto the kinase domain (Meng,2002) but the negative residues are solvent exposed. There are indications that further negative charges may play a role (la Cour,2004). Solved CRM1-NES complexes (Monecke,2009; Dong,2009) show that a number of complementary positively charged residues are spaced around the NES-binding groove. The structures also show most of the NES peptide is helical when bound, indicating that proline cannot occur in some of the less conserved positions. With additional structures being solved it became clear that there are five hydrophobic pockets in CRM1. Forward orientation NESes may occupy all five pockets (P0-P4) or may only occupy four hydrophobic pockets, omitting either P0 or P4. Because of this variability, searching for NESes typically used only four hydrophobic positions such as Φ1-(x)2–3-Φ2-(x)2–3-Φ3-x-Φ4 (Lee,2019). This is the case for the current NES forward motif in ELM and therefore it may fail to discover the all-helical NES variants that would not have that spacing. |
| Pattern: | ([DEQ].{0,1}[LIM].{2,3}[LIVMF][^P]{2,3}[LMVF].[LMIV].{0,3}[DE])|([DE].{0,1}[LIM].{2,3}[LIVMF][^P]{2,3}[LMVF].[LMIV].{0,3}[DEQ]) |
| Pattern Probability: | 0.0007626 |
| Present in taxon: | Eukaryota |
| Interaction Domain: |
Xpo1 (PF08389)
Exportin 1-like protein
(Stochiometry: 1 : 1)
PDB Structure: 1M5I
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