Molecular mechanisms of protein export by the malaria parasite plasmodium falciparum

Bana, Bianca (2022) Molecular mechanisms of protein export by the malaria parasite plasmodium falciparum. PhD thesis, Birkbeck, University of London.

Abstract

Upon invasion of a human red blood cell, the Plasmodium falciparum parasite exports hundreds of proteins into the host cell to alter its physical properties to promote parasite survival and propagation of infection. As these extensive modifications of red blood cells lead to the life-threatening development of severe malaria, a thorough understanding of molecular mechanisms of protein export may aid in developing novel antimalarial therapies that prevent severe pathogenesis. Here we dissect sequences in PEXEL-negative proteins that determine protein export, by investigating the trafficking of Pf332, SBP1, MAHRP2, and SURFIN. Interestingly, we demonstrate that the internal hydrophobic segment of Pf332 does not integrate into the membrane as a transmembrane domain, yet plays an essential role in targeting Pf332 to the secretory pathway. As Pf332 lacks a signal sequence and a membrane-integrating transmembrane domain, the protein exhibits a non-canonical mechanism of targeting to the ER. Additionally, despite containing a putative transmembrane segment, Pf332 is likely trafficked as a soluble protein in the parasite. We also find that SBP1 is extracted from an internal parasite membrane and likely forms a soluble intermediate during export, which is an exciting finding that suggests an unconventional trafficking pathway for membrane proteins in the parasite. Moreover, we demonstrate that the N-terminal and transmembrane domains of SBP1 and MAHRP2 are important determinants for protein targeting and trafficking. Additionally, we determine that a sequence within the extracellular domain of PEXEL surface antigen RIFIN targets the protein to the red blood cell plasma membrane, thus providing a foundation for ascertaining sequences in parasite membrane proteins which target to the red blood cell membrane.

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