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Sequence elements within the PEXEL motif and its downstream region modulate PTEX dependent protein export in Plasmodium falciparum .
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  • Paul R. Gilson,
  • Mikha Gabriela,
  • Claudia B. G. Barnes,
  • Dickson Leong,
  • Brad E. Sleebs,
  • Molly P. Schneider,
  • Dene R. Littler,
  • Brendan S. Crabb,
  • Tania F. de Koning-Ward
Paul R. Gilson
Burnet Institute

Corresponding Author:paul.gilson@burnet.edu.au

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Mikha Gabriela
Burnet Institute
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Claudia B. G. Barnes
Burnet Institute
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Dickson Leong
Burnet Institute
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Brad E. Sleebs
Walter and Eliza Hall Institute of Medical Research
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Molly P. Schneider
Burnet Institute
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Dene R. Littler
Monash University Monash Biomedicine Discovery Institute
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Brendan S. Crabb
Burnet Institute
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Tania F. de Koning-Ward
Deakin University School of Medicine
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Abstract

The parasite Plasmodium falciparum causes the most severe form of malaria and to invade and replicate in red blood cells (RBCs), it exports hundreds of proteins across the encasing parasitophorous vacuole membrane (PVM) into this host cell. The exported proteins help modify the RBC to support rapid parasite growth and avoidance of the human immune system. Most exported proteins possess a conserved Plasmodium Export Element (PEXEL) motif with the consensus RxLxE/D/Q amino acid sequence, which acts as a proteolytic cleavage recognition site within the parasite’s endoplasmic reticulum (ER). Cleavage occurs after the P 1 L residue and is thought to help release the protein from the ER so it can be putatively escorted by the HSP101 chaperone to the parasitophorous vacuole space surrounding the intraerythrocytic parasite. HSP101 and its cargo are then thought to assemble with the rest of a Plasmodium Translocon for Exported proteins (PTEX) complex, that then recognises the xE/D/Q capped N terminus of the exported protein and translocates it across the vacuole membrane into the RBC compartment. Here, we present evidence that supports a dual role for the PEXEL’s conserved P 2’ position E/Q/D residue, firstly, for plasmepsin V cleavage in the ER, and secondly, for efficient PTEX mediated export across the PVM into the RBC. We also present evidence that the downstream ‘spacer’ region separating the PEXEL motif from the folded functional region of the exported protein controls cargo interaction with PTEX as well. The spacer must be of a sufficient length and permissive amino acid composition to engage the HSP101 unfoldase component of PTEX to be efficiently translocated into the RBC compartment.
23 Mar 2023Submitted to Traffic
23 Mar 2023Submission Checks Completed
23 Mar 2023Assigned to Editor
31 Mar 2023Review(s) Completed, Editorial Evaluation Pending
03 Apr 2023Reviewer(s) Assigned
06 Jun 2023Editorial Decision: Revise Minor
24 Aug 20231st Revision Received
24 Aug 2023Submission Checks Completed
24 Aug 2023Assigned to Editor
24 Aug 2023Review(s) Completed, Editorial Evaluation Pending
28 Aug 2023Reviewer(s) Assigned
15 Oct 2023Editorial Decision: Accept