SRP54

PF3D7_1450100 (SRP54) is a subunit of the P. falciparum signal recognition particle, a ribonucleoprotein complex composed of six polypeptides (SRP9, SRP14, SRP19, SRP54, SRP68, SRP72) assembled on a 303 nt SRP RNA (PMID:24434517). In transgenic parasites, an SRP54-GFP fusion displays nucleo-cytoplasmic localization, indicating that SRP54 shuttles between the nucleus and cytoplasm (PMID:24434517). This nuclear import depends on the importin α/β pathway: ivermectin, an inhibitor of importin α/β-mediated import, blocks nuclear entry of SRP polypeptides including SRP54 at submicromolar concentrations and kills parasites (PMID:24434517). Beyond its membership in the SRP complex and its importin-dependent shuttling behavior, no direct biochemical or functional characterization of SRP54's role in co-translational protein translocation has been established for this gene in the available corpus.

1. 2007 Low

   Before any experimental work, it was unknown whether P. falciparum encodes SRP machinery; genome analysis established SRP54 as a predicted component of the parasite's SRP-mediated co-translational translocation pathway.

   Evidence Bioinformatic/genome analysis identifying an SRP54 homologue alongside SRP RNA and other SRP subunits

   PMID:17919451

   Open questions at the time

   • Computational prediction only, no experimental validation of SRP54 function or complex membership
   • Predicted SRP receptor partner not experimentally confirmed
   • No demonstration that the homologue is expressed or assembled into a particle
2. 2014 Medium

   To move beyond prediction, the SRP complex was characterized and SRP54's subcellular behavior was determined, establishing it as a bona fide six-polypeptide complex subunit that unexpectedly shuttles between nucleus and cytoplasm.

   Evidence SRP complex composition analysis and live-imaging co-localization of an SRP54-GFP fusion in transgenic parasites

   PMID:24434517

   Open questions at the time

   • Single lab, single localization method; no orthogonal confirmation of complex stoichiometry
   • Functional consequence of nuclear shuttling for SRP54 not defined
   • No direct evidence that SRP54 performs co-translational targeting in the parasite
3. 2014 Medium

   The route of SRP54 nuclear import was addressed pharmacologically, showing dependence on the importin α/β pathway and linking this trafficking step to parasite viability.

   Evidence Ivermectin and other import/export inhibitor treatment of transgenic GFP-SRP parasites with localization and viability readouts

   PMID:24434517

   Open questions at the time

   • Ivermectin effect is pharmacological and may act on multiple importin cargoes, so lethality cannot be attributed solely to SRP54 mislocalization
   • Direct interaction between SRP54 and importin α/β not demonstrated
   • The import signal within SRP54 was not mapped

• It remains unknown whether P. falciparum SRP54 performs the canonical signal-peptide recognition and co-translational translocation activity, and what its nuclear shuttling accomplishes mechanistically.
• No direct assay of SRP54 signal-sequence binding or GTPase/SRP receptor engagement in the parasite
• Functional role of nucleo-cytoplasmic shuttling uncharacterized
• No genetic loss-of-function data for SRP54 specifically