title: The Plasmodium falciparum exportome contains non-canonical PEXEL/HT proteins.
abstract: The pathogenicity of Plasmodium falciparum is partly due to parasite-induced host cell modifications. These modifications are facilitated by exported P. falciparum proteins, collectively referred to as the exportome. Export of several hundred proteins is mediated by the PEXEL/HT, a protease cleavage site. The PEXEL/HT is usually comprised of five amino acids, of which R at position 1, L at position 3 and E, D or Q at position 5 are conserved and important for export. Non-canonical PEXEL/HTs with K or H at position 1 and/or I at position 3 are presently considered non-functional. Here, we show that non-canonical PEXEL/HT proteins are overrepresented in P. falciparum and other Plasmodium species. Furthermore, we show that non-canonical PEXEL/HTs can be cleaved and can promote export in both a REX3 and a GBP reporter, but not in a KAHRP reporter, indicating that non-canonical PEXEL/HTs are functional in concert with a supportive sequence environment. We then selected P. falciparum proteins with a non-canonical PEXEL/HT and show that some of these proteins are exported and that their export depends on non-canonical PEXEL/HTs. We conclude that PEXEL/HT plasticity is higher than appreciated and that non-canonical PEXEL/HT proteins cannot categorically be excluded from Plasmodium exportome predictions.
authors: University of Hamburg, Institute of Zoology, Martin-Luther-King-Platz 3, D-20146, Hamburg, Germany.
authors: Jana
authors: J
authors: Schulze
authors: Department of Clinical Chemistry, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany.
authors: Marcel
authors: M
authors: Kwiatkowski
authors: University of Hamburg, Institute of Zoology, Martin-Luther-King-Platz 3, D-20146, Hamburg, Germany.
authors: Janus
authors: J
authors: Borner
authors: Department of Clinical Chemistry, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany.
authors: Hartmut
authors: H
authors: Schlüter
authors: Bernhard Nocht Institute for Tropical Medicine, Bernhard-Nocht-Str. 74, D-20359, Hamburg, Germany.
authors: Iris
authors: I
authors: Bruchhaus
authors: University of Hamburg, Institute of Zoology, Martin-Luther-King-Platz 3, D-20146, Hamburg, Germany.
authors: Thorsten
authors: T
authors: Burmester
authors: Bernhard Nocht Institute for Tropical Medicine, Bernhard-Nocht-Str. 74, D-20359, Hamburg, Germany.
authors: Tobias
authors: T
authors: Spielmann
authors: University of Hamburg, Institute of Zoology, Martin-Luther-King-Platz 3, D-20146, Hamburg, Germany.
authors: Christian
authors: C
authors: Pick
mesh_terms: D020816:Amino Acid Motifs; D006790:Host-Parasite Interactions; D010447:Peptide Hydrolases / Q000378:metabolism; D010963:Plasmodium falciparum / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D015800:Protozoan Proteins / Q000378:metabolism*
chemical_list: D015800:Protozoan Proteins; D010447:Peptide Hydrolases