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Abstract
Tail-anchored (TA) proteins are defined by the absence of N-terminus signal sequence and the presence of a single transmembrane domain (TMD) proximal to their C-terminus. They play fundamental roles in cellular processes including vesicular trafficking, protein translocation and quality control. Some of the TA proteins are post-translationally integrated by the Guided Entry of TA (GET) pathway to the cellular membranes; with their N-terminus oriented towards the cytosol and C-terminus facing the organellar lumen. The TA repertoire and the GET machinery have been extensively characterized in the yeast and mammalian systems, however, they remain elusive in the human malaria parasite Plasmodium falciparum. In this study, we bioinformatically predicted a total of 63 TA proteins in the P. falciparum proteome and revealed the association of a subset with the P. falciparum homolog of Get3 (PfGet3). In addition, our proximity labelling studies either definitively identified or shortlisted the other eligible GET constituents, and our in vitro association studies validated associations between PfGet3 and the corresponding homologs of Get4 and Get2 in P. falciparum. Collectively, this study reveals the presence of proteins with hallmark TA signatures and the involvement of evolutionary conserved GET trafficking pathway for their targeted delivery within the parasite.
Highlights
Integral membrane proteins constitute ~20–30% of the total eukaryotic proteome where they serve essential cellular functions including vesicular sorting, solute transport, protein homeostasis and organelle biosynthesis
Tail-anchored (TA) membrane proteins are known to play essential cellular functions in the eukaryotes. These proteins are trafficked to their respective destinations by post-translational translocation pathways that are evolutionarily conserved from yeast to human. They remain unidentified in the malaria parasite Plasmodium falciparum
Multiple pathways are implicated in the targeting of TA proteins destined for the ER, including a promiscuous ‘moonlighting function’ by the signal recognition particle (SRP)/Sec61 translocon [21, 22], insertion mediated by the SRP-independent targeting (SND) components [23], non-assisted delivery and insertion of TA proteins regulated by the cytosolic factors [24] and the components of the ER membrane complex (EMC) [25, 26]
Summary
Integral membrane proteins constitute ~20–30% of the total eukaryotic proteome where they serve essential cellular functions including vesicular sorting, solute transport, protein homeostasis and organelle biosynthesis. Tail-anchored (TA) proteins are one such unique class of integral membrane proteins characterized by the absence of any N-terminus signal sequence (SS) and the presence of a single helical transmembrane domain (TMD) at or near their C-terminus (CTS) [9]. This close proximity of the TMDs in TA proteins places it within the ribosomal tunnel, precluding SRP/Sec61-mediated co-translational insertion; and TA proteins must target in a strictly post-translational manner [10,11,12]. As compared to ER-localized TA proteins, mitochondrial-destined TA proteins tend to possess TMDs that are shorter and less hydrophobic, and their CTSs are enriched in positively charged amino acid residues [13]
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