Affinage · Plasmodium

PF3D7_0517300

serine/arginine-rich splicing factor 1

Annotated
2026-09-07
7 papers in source corpus 7 papers cited in narrative 7 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PF3D7_0517300 (PfSR1/PbSR1) is a serine/arginine-rich splicing factor that governs RNA processing in malaria parasites, functioning analogously to mammalian SRSF1 by mediating constitutive and alternative splicing and additionally regulating steady-state mRNA levels (PMID:22885299, PMID:25807998). It engages RNA through two RRM domains with complementary sequence preferences: the N-terminal RRM1 recognizes pyrimidines through a conserved tyrosine and glutamate that specify a cytosine 5' of pyrimidines with a 3' pyrimidine inserted into a positively charged pocket, while the C-terminal pseudo-RRM (RRM2) binds purines non-canonically and with higher affinity (PMID:30500338). Endogenously, PfSR1 binds transcripts bearing specific sequence motifs and controls both their splicing and abundance in vivo, acting from a nuclear position adjacent to Nuclear Pore Complex clusters (PMID:25807998). Its RS domain is required for nuclear localization (PMID:22885299), and its RNA-binding activity is modulated by phosphorylation by the splicing-related kinase PfSRPK1 (PMID:20870716). Proper regulation of the factor is required for asexual proliferation in erythrocytes, and its P. berghei ortholog is essential for asexual development (PMID:22885299, PMID:34604117). Beyond splicing, PfSR1 has an unexpected role in the DNA damage response: it is recruited to DNA damage foci and, while dispensable for basal viability, is required for parasite recovery from DNA-damaging agents and from artemisinin (PMID:34291805). In P. berghei, PbSR1 localizes to both nucleus and cytoplasm and, in addition to nuclear RNA-binding partners and small nuclear ribonucleoproteins, co-localizes with the rhoptry proteins RhopH1/2/3 in the cytoplasm of trophozoites and gametocytes (PMID:41634752).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2010 Medium

    Establishing that PF3D7_0517300 is an RNA-binding protein and a kinase substrate placed it in a splicing-regulatory context and identified an upstream regulator of its activity.

    Evidence In vitro kinase assay, RNA-binding assay, and nuclear fractionation in P. falciparum

    PMID:20870716

    Open questions at the time
    • Phosphosites on PfSR1 not mapped
    • Functional consequence of PfSRPK1 phosphorylation on splicing not tested in vivo
  2. 2012 High

    Demonstrating splicing activity, RS-domain-dependent nuclear localization, and a proliferation requirement defined PF3D7_0517300 as a bona fide SR splicing factor essential for the parasite.

    Evidence In vitro splicing, mini-gene reporters, RS-domain deletion, and inducible overexpression in P. falciparum

    PMID:22885299

    Open questions at the time
    • Direct endogenous splicing targets not yet identified
    • Mechanism linking splicing defects to proliferation loss unresolved
  3. 2015 High

    Identifying endogenous RNA targets and a bound sequence motif showed PF3D7_0517300 regulates both alternative splicing and steady-state mRNA levels from a position at the nuclear periphery.

    Evidence RIP-chip, RNA-EMSA, and live-cell imaging near NPC clusters in P. falciparum

    PMID:25807998

    Open questions at the time
    • Functional consequence of NPC-adjacent localization not mechanistically dissected
    • How motif recognition selects splicing vs. mRNA-stability outcomes unknown
  4. 2018 High

    Structural and biophysical dissection of the two RRMs explained how PF3D7_0517300 achieves broad RNA recognition through complementary pyrimidine- and purine-preferring modules.

    Evidence NMR structure of RRM1–RNA complex, ITC, and chemical shift perturbation mapping in P. falciparum

    PMID:30500338

    Open questions at the time
    • Full-length tandem-RRM RNA complex not resolved
    • Structural basis of RRM2 non-canonical binding not directly determined
  5. 2021 High

    An inducible/reversible system revealed a moonlighting role in the DNA damage response, showing PF3D7_0517300 is recruited to damage foci and required for recovery from genotoxic and artemisinin stress despite being dispensable for basal viability.

    Evidence Inducible/reversible knockdown, immunofluorescence of damage foci, and DNA-damaging-agent/artemisinin challenge in P. falciparum

    PMID:34291805

    Open questions at the time
    • Molecular mechanism linking an SR splicing factor to DNA repair unresolved
    • Whether the repair role depends on RNA binding or splicing activity not determined
  6. 2021 Medium

    Genetic loss-of-function in P. berghei confirmed the ortholog's essentiality for asexual development, distinguishing it from other mRNA-export/RNA-binding factors that were dispensable.

    Evidence Genetic knockout/knockdown with developmental phenotyping in P. berghei

    PMID:34604117

    Open questions at the time
    • Stage of developmental arrest not molecularly characterized
    • Whether essentiality reflects splicing function specifically not addressed
  7. 2026 Medium

    Interactome and imaging in P. berghei extended the factor's associations beyond nuclear RNA machinery to an unexpected cytoplasmic co-localization with rhoptry proteins in specific developmental stages.

    Evidence IP-MS of GFP-tagged PbSR1 and live-cell co-imaging with RhopH2 in P. berghei ANKA

    PMID:41634752

    Open questions at the time
    • Functional significance of the RhopH interaction unknown
    • Whether cytoplasmic association is direct or indirect not established
    • Stage-specificity mechanism unexplained

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PF3D7_0517300 mechanistically bridges its established splicing/mRNA-regulatory function to its DNA damage response role and its cytoplasmic rhoptry-protein association remains unresolved.
  • No mechanism connecting splicing activity to DNA repair recruitment
  • Functional role of RhopH co-localization untested
  • Cross-species reconciliation of nuclear vs. cytoplasmic roles absent

Mechanism profile

Synthesis pass · controlled-vocabulary classification
Partners
NUCLEAR RNA-BINDING PROTEINS AND SMALL NUCLEAR RIBONUCLEOPROTEINS (P. BERGHEI IP-MS)PFSRPK1 (KINASE, PHOSPHORYLATES PFSR1; P. FALCIPARUM)RHOPH1/CLAG3 (P. BERGHEI, CYTOPLASMIC CO-LOCALIZATION)RHOPH2 (P. BERGHEI, CYTOPLASMIC CO-LOCALIZATION)RHOPH3 (P. BERGHEI)

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 PfSR1 (PF3D7_0517300) was identified as a substrate of PfSRPK1 (a novel P. falciparum splicing-related kinase); PfSR1 interacts with RNA, and PfSRPK1 modulates PfSR1's RNA binding activity. Both PfSRPK1 and PfSR1 localize to the nucleus early in parasite development. In vitro kinase assay (substrate identification), RNA-binding assay, nuclear fractionation/localization The Journal of biological chemistry Medium 20870716
2012 PfSR1 can mediate RNA splicing in vitro and functions as an alternative splicing factor in mini-gene in vivo systems, similar to mammalian SRSF1. The predicted RS domain of PfSR1 is essential for its localization to the nucleus. Over-expression of pfsr1 influences alternative splicing of P. falciparum genes in vivo, and proper regulation of pfsr1 is required for parasite proliferation in human RBCs. In vitro splicing assay, mini-gene reporter system, PfSR1-myc tagging with live-cell imaging, RS-domain deletion mutagenesis, inducible overexpression with AS analysis Nucleic acids research High 22885299
2015 PfSR1 localizes adjacent to Nuclear Pore Complex (NPC) clusters in the nucleus of early-stage parasites. RNA immunoprecipitation followed by microarray (RIP-chip) identified endogenous RNA targets of PfSR1; bioinformatic analysis revealed common sequence motifs, and RNA-EMSAs confirmed PfSR1 preferentially binds RNA molecules containing these motifs. PfSR1 regulates not only alternative splicing but also steady-state mRNA levels of transcripts containing these motifs in vivo. Live-cell imaging/fluorescence microscopy, RIP-chip (RNA immunoprecipitation + microarray), RNA-EMSA, inducible overexpression system Molecular microbiology High 25807998
2021 PfSR1 plays an unexpected role in DNA repair in P. falciparum: using an inducible and reversible expression system, PfSR1 was shown to be recruited to foci of DNA damage. Loss of PfSR1 does not impair basal parasite viability but is essential for recovery from DNA-damaging agents and from artemisinin exposure, establishing PfSR1 as required for the DNA damage response. Inducible/reversible knockdown system, immunofluorescence assay for DNA damage foci recruitment, DNA-damaging agent and artemisinin challenge assays Journal of cell science High 34291805
2021 SR1 (P. berghei ortholog of PF3D7_0517300) is essential for asexual development of malaria parasites. NAB2 and SR1 (but not THO4, NPL3, or GBP2) play essential roles in asexual development of P. berghei. Genetic knockout/knockdown with developmental phenotype assessment in P. berghei Frontiers in cellular and infection microbiology Medium 34604117
2018 The N-terminal RRM1 of PfSR1 recognizes RNA with semi-specificity for pyrimidines: a conserved tyrosine on β1 and a glutamate on β4 mediate specific recognition of a cytosine 5' of one or more pyrimidines, while affinity is conferred by insertion of a 3' pyrimidine into a positively charged pocket. RRM1 binds RNA with moderate affinity and retains fast dynamics. The purine preference of PfSR1 was ascertained to reside in the C-terminal pseudo-RRM (RRM2), which binds RNA non-canonically and with greater affinity than RRM1. The two RRMs thus show complementary RNA sequence recognition. NMR solution structure of RRM1–RNA complex, isothermal titration calorimetry (ITC), NMR chemical shift perturbation mapping, site-specific mutagenesis inference from structural data Journal of molecular biology High 30500338
2026 PbSR1 (P. berghei ortholog of PF3D7_0517300) localizes predominantly to the nucleus but also to the cytoplasm. IP-MS identified PbSR1 interacting partners including nuclear RNA-binding proteins and small nuclear ribonucleoproteins, as well as cytoplasmic rhoptry proteins RhopH1 (Clag3), RhopH2, and RhopH3. Live-cell imaging showed co-localization of PbSR1 and RhopH2 in the cytoplasm of trophozoites and gametocytes but not in mature schizonts or merozoites. Immunoprecipitation coupled to mass spectrometry (IP-MS) of GFP-tagged PbSR1, live-cell fluorescence imaging of co-expressed PbSR1::GFP and RhopH2::mCherry, western blot Malaria journal Medium 41634752

Source papers

Stage 0 corpus · 7 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 PfSRPK1, a novel splicing-related kinase from Plasmodium falciparum. The Journal of biological chemistry 31 20870716
2012 A novel Plasmodium falciparum SR protein is an alternative splicing factor required for the parasites' proliferation in human erythrocytes. Nucleic acids research 29 22885299
2015 PfSR1 controls alternative splicing and steady-state RNA levels in Plasmodium falciparum through preferential recognition of specific RNA motifs. Molecular microbiology 18 25807998
2021 An SR protein is essential for activating DNA repair in malaria parasites. Journal of cell science 10 34291805
2021 Roles and Cellular Localization of GBP2 and NAB2 During the Blood Stage of Malaria Parasites. Frontiers in cellular and infection microbiology 6 34604117
2018 The N-terminal RNA Recognition Motif of PfSR1 Confers Semi-specificity for Pyrimidines during RNA Recognition. Journal of molecular biology 2 30500338
2026 Identification of serine/arginine-rich splicing factor 1-interacting proteins in Plasmodium berghei. Malaria journal 0 41634752