SRP14

PF3D7_1203200 (SRP14) is the protein component of the Alu domain of the P. falciparum signal recognition particle, a ribonucleoprotein complex of six polypeptides (SRP9, SRP14, SRP19, SRP54, SRP68, SRP72) assembled on a 303 nt SRP RNA (PMID:24434517). SRP14 forms a compact, folded globular heterodimer with SRP9 (PfSRP9/14), which together with the PfAlu RNA constitutes the PfAlu domain; unlike its human counterpart, PfSRP14 carries an extended internal loop L1 (residues 35–70), and the intact PfAlu domain adopts an open Y-shaped conformation rather than the canonical closed form, yet is bound by P. falciparum cytoplasmic ribosomes with nanomolar affinity (PMID:34017052). In live parasites, GFP-tagged SRP14 shuttles between nucleus and cytoplasm, and its nuclear import is importin α/β-dependent and blocked by ivermectin at submicromolar concentrations, which kills the parasite (PMID:24434517). Beyond its structural role in the Alu domain, its ribosome-binding property, and its nucleo-cytoplasmic trafficking, no further mechanistic detail on PF3D7_1203200 has been characterized in the available corpus.

1. 2004 Low

   Before any experimental work, it was unknown whether P. falciparum even encoded an SRP Alu-domain protein; genome analysis answered this by identifying an SRP14 homolog, establishing the gene as a candidate SRP component.

   Evidence Comparative genomic/bioinformatic analysis of protozoan genomes, annotating the former hypothetical protein PFL0160w

   PMID:14720308

   Open questions at the time

   • Computational prediction only; no biochemical validation of the P. falciparum protein
   • Did not establish whether the predicted protein assembles into an SRP complex or binds RNA
2. 2014 Medium

   It was unknown where SRP14 resides in the parasite or whether its trafficking is druggable; live-parasite imaging placed SRP14 in a six-polypeptide SRP complex and showed importin-dependent nucleo-cytoplasmic shuttling that ivermectin blocks, linking SRP14 trafficking to parasite viability.

   Evidence Transgenic SRP14-GFP P. falciparum lines with co-localization microscopy and pharmacological ivermectin inhibition

   PMID:24434517

   Open questions at the time

   • Ivermectin acts on general importin α/β import, so the killing effect is not proven to be SRP14-specific
   • Functional role of nuclear localization for an SRP protein remains undefined
   • Assembly stoichiometry and order within the SRP complex not resolved
3. 2021 High

   The structural basis of the parasite Alu domain and how it differs from the human counterpart was unknown; multi-method structural analysis showed PfSRP14 forms a globular heterodimer with SRP9, carries a unique extended L1 loop, and yields an open Y-shaped Alu domain that nonetheless binds ribosomes with nanomolar affinity.

   Evidence NMR, SAXS, and cryo-EM of recombinant PfSRP9/14 and PfAlu RNA from E. coli, with ribosome-binding affinity measurements

   PMID:34017052

   Open questions at the time

   • Functional consequence of the open Y-shaped conformation for translational arrest was not tested
   • Role of the parasite-specific L1 loop not experimentally dissected
   • Structure of SRP14 within the full six-protein SRP was not determined

• Whether the SRP14-dependent Alu domain executes canonical elongation arrest during co-translational targeting in P. falciparum, and whether SRP14 itself is essential and druggable independent of general importin inhibition, remains unresolved.
• No functional assay directly linking SRP14 to translational arrest or protein targeting in the parasite
• No SRP14-specific genetic knockout/knockdown phenotype reported
• Physiological significance of nuclear localization for SRP14 unestablished