The Eukaryotic Linear Motif resource for
Functional Sites in Proteins
Functional site class:
Apicomplexan export motif
Functional site description:
Apicomplexan parasites are unicellular eukaryotes responsible for various animal and human diseases. They invade host cells, remodel them and proliferate intracellularly thanks to the coordinated secretion of proteins. These proteins are exported through different peptide signals (e.g. PEXEL, TEXEL, and signal peptide) and protein complexes.
ELM Description:
Plasmodium falciparum is the causative agent of the most lethal form of Malaria in humans. It invades and multiplies inside the liver and erythrocytic cells. After infection, this parasite hijacks the cell by exporting a wide range of proteins into the cytosol and cell membrane from a so-called Parasitophorous vacuole (PV). To coordinate protein secretion, it makes use of different peptide signals and protein complexes (de Koning-Ward,2016).
The Plasmodium Export Element (PEXEL) is a 5-residue trafficking motif used among Plasmodium species. It is located near the N-terminus of exported proteins after an endoplasmic reticulum (ER) targeting signal peptide. It is formed by the conserved sequence RxLx(EDQ). It is recognised and cleaved in the parasite’s ER lumen by the aspartyl protease Plasmepsin V (PMV) working together with other proteins (Pool,2018). Proteolytic cleavage happens between the third and fourth positions after the conserved leucine (RxL↓x(EDQ)). The newly created N-terminus is acetylated (AC-xE/D/Q) co-translationally or soon after (de Koning-Ward,2016). The remaining conserved residues after the cleavage site play a role in the protein processing and export. Proteins are finally exported into the cell cytosol through the PTEX multiprotein translocon complex spanning the PV membrane (PVM) (Boddey,2010; Marti,2013; Pool,2018).
Previous studies have demonstrated the essentiality of the position -3 R and position -1 L for PMV cleavage (Boddey,2013). Mutations of the arginine or leucine to alanine traps proteins in the ER, while mutations at +2 trap them in the PV (Boddey,2009). Nevertheless, there are many non-canonical functional instances of PEXEL with Lysine in the first position or with Isoleucine in the third, and relaxed versions with two permissive positions (RxLxxE) after the third residue. In these variations, the surrounding environment of the motif might play a role in its recognition (Schulze,2015; Pick,2011).
Pattern: (R.[LI].[EDQ])|(R.L..[EDQ])|(K.L.E)
Pattern Probability: 0.0021605
Present in taxon: Plasmodium
Interaction Domain:
Asp (PF00026) Eukaryotic aspartyl protease (Stochiometry: 1 : 1)
o See 24 Instances for TRG_Pf-PMV_PEXEL_1
o Abstract
The Apicomplexa phylum is comprised of unicellular eukaryotes, which are parasitic agents of various diseases in humans as well as in wild and domesticated animals. Among the most studied Apicomplexa species are the ones belonging to the genera Plasmodium, Toxoplasma, Babesia, Eimeria, Theileria and Sarcocystis (Arisue,2015). Infection of most Apicomplexa is characterized by an apical complex specialisation, substrate-dependent Glideosome mobility, the formation of a parasitophorous vacuole (PV) from the invagination of host cells, and a multicomponent secretory system (White,2018). From the non-fusogenic PV these parasites are able to sequester nutrients and hijack their hosts’ molecular pathways in order to evade immune responses and clearance, remodel the cytoplasm and proliferate. These alterations are achieved by the coordinated export of parasite proteins into the host (Marti,2013).
The Plasmodium Export element (PEXEL) is the best studied trafficking motif in the Apicomplexan phylum and aids species of the Plasmodium parasites to mediate protein export. PEXEL has a dual function, as a cleavage motif recognised by the aspartyl protease Plasmepsin V and as a targeting motif to export processed proteins from the Endoplasmic Reticulum (ER) through the parasite and PV membranes into the infected cell cytosol (de Koning-Ward,2016) (Marti,2013). These proteins are often part of multi-copy gene families such as RIFINs (repetitive interspersed family) and STEVORs (subtelomeric variable open reading frames), but there are also more unique exported proteins (Pick,2011). In Plasmodium falciparum, the most lethal species for humans, PEXEL is present in around 400 exported proteins, representing ~8% of the parasite’s proteome, or ~80% of its exportome, from which 20% are predicted to be essential (de Koning-Ward,2016). The rest of the exported proteins which lack conserved elements are termed PEXEL-negative proteins (PNEPs). It has been proposed that they might associate with other proteins that contain PEXEL in order to be exported (Kumar,2018).
Other Plasmodium species have somewhat more divergent and flexible PEXEL motifs which have not been annotated yet. The Toxoplasma gondii trafficking and cleavage motif, TEXEL, is typically RRL; it is not yet in ELM.
o 9 selected references:

o 10 GO-Terms:

o 24 Instances for TRG_Pf-PMV_PEXEL_1
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
Q9U5L9 PF3D7_0300400
48 52 KRTTIKSRLLAQTQIHNPHY TP 2 Plasmodium falciparum 3D7
Q8I2C7 PF3D7_0115300
36 40 PHHTQTNRSLCECDTQSTNY TP 4 Plasmodium falciparum 3D7
Q8I0U6 PF3D7_0102200
86 91 QFTDRCSRNLYGETLPVNPY TP 5 Plasmodium falciparum 3D7
Q9TY99 PF3D7_0202000
54 58 SFDFRNKRTLAQKQHEHHHH TP 5 Plasmodium falciparum 3D7
84 88 DYGFRESRILAEGEDTCARK TP 5 Plasmodium falciparum 3D7
Q8I2F7 PF3D7_0936300
46 50 SYEGSSFRQLSEPVVEEQDL TP 4 Plasmodium falciparum 3D7
Q8IEQ3 PF3D7_1306200
70 74 GKNNKCYRYIQEALYDPNIQ TN 1 Plasmodium falciparum 3D7
Q8I2B3 PF3D7_0102700
82 86 LVLQNDERNILQEKHSNWNE TN 1 Plasmodium falciparum 3D7
Q8I631 PF3D7_1201400
51 55 IVKLKNRKILSELSDVQLED TN 1 Plasmodium falciparum 3D7
Q8I637 PF3D7_1200800
46 50 VSYDRPSKCLSENSKHHVNS TN 1 Plasmodium falciparum 3D7
Q9U0N3 PF3D7_0112800
48 52 IDINRFKRIIAEASEEQKYP TP 2 Plasmodium falciparum 3D7
Q8I636 PF3D7_1200900
71 75 ELDRKYSKMLCELYTSNRDY TP 1 Plasmodium falciparum 3D7
Q8I2F2 PF3D7_0936800
57 61 HCNKRHFKSLAEASPEEHNN TP 6 Plasmodium falciparum 3D7
O97336 PF3D7_0301700
86 90 ILGIRINKSLAEMDHTKYHP TP 5 Plasmodium falciparum 3D7
Q8IDG9 PF3D7_1353100
86 90 TQGLSKGRILTQGDHHEETE TP 2 Plasmodium falciparum 3D7
Q8IK20 PF3D7_1001600
86 90 KIVDRYTRKLAEALKDDERF TP 2 Plasmodium falciparum 3D7
Q8I490 PF3D7_0501000
89 93 TFNRRDTRVLAEQEDQYIRN TP 2 Plasmodium falciparum 3D7
Q8I202 PF3D7_0402400
59 63 SQRLKEYRILVEFSNSYYYD TP 2 Plasmodium falciparum 3D7
Q8I298 PF3D7_0104200
61 65 YKNKIKSRILKENKEESLET TP 2 Plasmodium falciparum 3D7
P02895 GBP
84 88 DYGFRESRILAEGEDTCARK TP 5 Plasmodium falciparum FCR-3/Gambia
P05227 Histidine-rich protein PFHRP-II
45 49 KGLNLNKRLLHETQAHVDDA TP 2 Plasmodium falciparum (Malaria parasite P. falciparum)
Q8I489 PF3D7_0501100.1
60 64 VFDFTSLRSLAEFNSGSSRE TP 1 Plasmodium falciparum 3D7
Q8I492 PF3D7_0500800
75 79 NNNDRYVRILSETEPPMSLE TP 1 Plasmodium falciparum 3D7
P09346 Knob-associated histidine-rich protein
54 58 SFDFRNKRTLAQKQHEHHHH TP 2 Plasmodium falciparum FCR-3/Gambia
Please cite: The eukaryotic linear motif resource - 2018 update. (PMID:29136216)

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