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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 <jats:italic>Plasmodium<\/jats:italic> 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<jats:sub>1<\/jats:sub> 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 <jats:italic>Plasmodium<\/jats:italic> translocon for exported proteins (PTEX) complex, that then recognises the xE\/D\/Q capped N\u2010terminus 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<jats:sub>2<\/jats:sub>\u2032 position E\/Q\/D residue, first, for plasmepsin V cleavage in the ER, and second, for efficient PTEX mediated export across the PVM into the RBC. We also present evidence that the downstream \u2018spacer\u2019 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.<\/jats:p>","DOI":"10.1111\/tra.12922","type":"journal-article","created":{"date-parts":[[2023,11,6]],"date-time":"2023-11-06T05:46:11Z","timestamp":1699249571000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Sequence elements within the <scp>PEXEL<\/scp> motif and its downstream region modulate <scp>PTEX\u2010dependent<\/scp> protein export in <i>Plasmodium falciparum<\/i>"],"prefix":"10.1111","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8983-9790","authenticated-orcid":false,"given":"Mikha","family":"Gabriela","sequence":"first","affiliation":[{"name":"Malaria Virulence and Drug Discovery Group Burnet Institute  Melbourne Victoria Australia"},{"name":"School of Medicine Deakin University  Geelong Victoria Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudia B. G.","family":"Barnes","sequence":"additional","affiliation":[{"name":"Malaria Virulence and Drug Discovery Group Burnet Institute  Melbourne Victoria Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dickson","family":"Leong","sequence":"additional","affiliation":[{"name":"Malaria Virulence and Drug Discovery Group Burnet Institute  Melbourne Victoria Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brad E.","family":"Sleebs","sequence":"additional","affiliation":[{"name":"The Walter and Eliza Hall Institute of Medical Research  Parkville Victoria Australia"},{"name":"Department of Medical Biology The University of Melbourne  Parkville Victoria Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5491-5455","authenticated-orcid":false,"given":"Molly Parkyn","family":"Schneider","sequence":"additional","affiliation":[{"name":"Malaria Virulence and Drug Discovery Group Burnet Institute  Melbourne Victoria Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dene R.","family":"Littler","sequence":"additional","affiliation":[{"name":"Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute Monash University  Clayton Victoria Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brendan S.","family":"Crabb","sequence":"additional","affiliation":[{"name":"Malaria Virulence and Drug Discovery Group Burnet Institute  Melbourne Victoria Australia"},{"name":"Department of Medical Biology The University of Melbourne  Parkville Victoria Australia"},{"name":"Department of Microbiology and Immunology University of Melbourne  Parkville Victoria Australia"},{"name":"Department of Immunology Monash University  Melbourne Victoria Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tania F.","family":"de Koning\u2010Ward","sequence":"additional","affiliation":[{"name":"School of Medicine Deakin University  Geelong Victoria Australia"},{"name":"Institute for Mental and Physical Health and Clinical Translation (IMPACT) Deakin University  Geelong Victoria Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul R.","family":"Gilson","sequence":"additional","affiliation":[{"name":"Malaria Virulence and Drug Discovery Group Burnet Institute  Melbourne Victoria Australia"},{"name":"Department of Microbiology and Immunology University of Melbourne  Parkville Victoria 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