The Eukaryote Linear Motif resource for Functional Sites in Proteins
Accession:
Functional site class:
NES Nuclear Export Signal
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 nucleus and cytoplasm. In such proteins, availability 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.
ELM Description:
Accessible peptides matching the leucine-rich nuclear export signal (NES) bind to the CRM1 exportin protein. The fungicide Leptomycin B (LMB) specifically inhibits this export pathway. Since the NES has been reported as four 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 (Kadlec,2004). While some of the reported NES peptides are unlikely to be true, more proteins will undoubtedly be found to 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 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 charge 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.
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
<a href="http://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=1M5I" title="" target="_blank"><img src="/media/pdb.ico.png"/>1M5I</a>
o See 18 Instances for TRG_NES_CRM1_1
o Abstract
The import-export protein traffic through the nuclear envelope is mediated by soluble transport receptors (carriers) termed importins and exportins that bind to specific signals present within their substrates. The best-characterized export carrier is CRM1 (also known as exportin1/Xpo1), an evolutionarily well-conserved protein. The CRM1-mediated export is inhibited by the fungicide leptomycin B (LMB), providing a unique experimental tool for studying nuclear localization and trafficking in eukaryotic cells. The NES signal was first identified in the HIV Rev protein and in the Protein Kinase A inhibitor (PKI-alpha). The majority of the export substrates of CRM1 contain a Leucine-rich Nuclear Export signal (NES) consisting of 4-5 hydrophobic residues in a region of ~ 10 amino acids. The NetNES 1.1 server predicts leucine-rich nuclear export signals (NES) in eukaryotic proteins using a combination of neural networks and hidden Markov models.
Genuine NES motifs appear to be always in regions of natively disordered peptide. Clashes with known globular domains should be assumed to indicate non-viability of the motif candidate. However, NES motifs can be found close in sequence to known domains and may conditionally bind to them in a closed conformation. Regulated accessibility of the NES may be important for many proteins that must stay in the nucleus until signalled to exit, for instance MapKapK2 (Meng,2002). Regulation of nuclear export may be more sophisticated than for import: one indication is that CRM1 is much more flexible and dynamic (and harder to crystallise without accessory proteins such as RAN) than importins, although being composed of similar HEAT repeat elements.
o 12 selected references:

o 4 GO-Terms:

o 18 Instances for TRG_NES_CRM1_1
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Protein NameGene NameStartEndSubsequenceLogic#Ev.OrganismNotes
STK4_HUMAN STK4 359 374 HDDTLPSQLGTMVINAEDEE TP 2 Homo sapiens (Human)
P73_HUMAN TP73 366 379 ENFEILMKLKESLELMELVP TP 2 Homo sapiens (Human)
CTND1_HUMAN CTNND1 942 956 GQESLEEELDVLVLDDEGGQ TP 2 Homo sapiens (Human)
1 
P53_HUMAN TP53 339 352 ERFEMFRELNEALELKDAQA TP 2 Homo sapiens (Human)
1 
CCNB1_XENLA ccnb1 106 121 LPDELCQAFSDVLIHVKDVD TP 2 Xenopus laevis (African clawed frog)
PER2_MOUSE Per2 459 470 PSVQELTEQIHRLLMQPVPH TP 2 Mus musculus (House mouse)
MP2K1_XENLA map2k1 31 44 TNLEALQKKLEELELDEQQR TP 2 Xenopus laevis (African clawed frog)
MAPK2_HUMAN MAPKAPK2 354 368 VKEEMTSALATMRVDYEQIK TP 3 Homo sapiens (Human)
SPN1_HUMAN SNUPN 2 17 MEELSQALASSFSVSQDLNS TP 3 Homo sapiens (Human)
REV_HV1C4 rev 74 87 VPLQLPPLERLTLDCSEDCG TP 2 Human immunodeficiency virus type 1 (CDC-451 ISOLATE)
APC_HUMAN APC 67 78 SGQIDLLERLKELNLDSSNF TP 2 Homo sapiens (Human)
APC_HUMAN APC 163 176 AQLQNLTKRIDSLPLTENFS TP 3 Homo sapiens (Human)
IPKA_HUMAN PKIA 37 51 SNELALKLAGLDINKTEGEE TP 2 Homo sapiens (Human)
NEP_I34A1 NS 10 22 SSFQDILLRMSKMQLESSSG TP 3 Influenza A virus (A/Puerto Rico/8/1934(H1N1))
REX_HTL1A 80 93 PSMDALSAQLYSSLSLDSPP TP 3 Human T-cell lymphotrophic virus type 1 (strain ATK)
PER1_MOUSE Per1 488 499 SDIQELSEQIHRLLLQPVHS TP 2 Mus musculus (House mouse)
MPIP3_HUMAN CDC25C 189 203 AEEISDELMEFSLKDQEAKV TP 2 Homo sapiens (Human)
1 
NEP_I34A1 NS 11 22 SSFQDILLRMSKMQLESSSG TP 3 Influenza A virus (A/Puerto Rico/8/1934(H1N1))
Please cite: The Eukaryotic Linear Motif Resource ELM: 10 Years and Counting (PMID:24214962)

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