PF3D7_1427900

PF3D7_1427900 (PfLRR1), the P. falciparum Sds22 orthologue, is a leucine-rich repeat regulator of protein phosphatase type 1 (PP1) that couples phosphatase control to cell cycle progression (PMID:16629662). It physically binds PfPP1 and directly inhibits its phosphatase activity in vitro (PMID:16629662), and when expressed in Xenopus oocytes it drives progression through the G2/M checkpoint by inducing germinal vesicle breakdown, an outcome phenocopied by pharmacological PP1 inhibition (PMID:16629662). This regulatory relationship is conserved in the rodent malaria parasite P. berghei, where the orthologue PbLRR1 complexes with and inhibits PbPP1 across both asexual and sexual stages, is required for normal oocyst development in the mosquito, and controls the phosphorylation status of PP1 Inhibitor 3 (I3), which is found within the PbLRR1/PbPP1 complex and becomes hypophosphorylated upon PbLRR1 depletion (PMID:35920043). Beyond its role as a PP1-inhibitory subunit acting through cell cycle progression and the I3 regulatory node, no further mechanistic detail for this gene has been characterized in the available corpus.

1. 2006 High

   Establishing whether PfLRR1 acts on the parasite phosphatase machinery, this work showed it is a direct physical and functional partner of PfPP1, defining it as a PP1 regulatory subunit rather than an orphan LRR protein.

   Evidence GST pull-down and co-immunoprecipitation from parasite extracts plus in vitro phosphatase activity assay, in P. falciparum

   PMID:16629662

   Open questions at the time

   • Interaction interface and stoichiometry not resolved
   • In vivo requirement in P. falciparum asexual growth not tested
   • No structural model of the PfLRR1-PfPP1 complex
2. 2006 Medium

   To connect the biochemical inhibition to a cellular process, heterologous expression showed PfLRR1 drives G2/M progression, linking PP1 inhibition to cell cycle checkpoint control.

   Evidence Xenopus oocyte expression with GVBD readout and okadaic acid / anti-PP1 antibody pharmacological controls, in P. falciparum

   PMID:16629662

   Open questions at the time

   • Effect demonstrated in a heterologous oocyte system, not in the parasite itself
   • Endogenous parasite cell cycle role not directly measured
   • Downstream substrates dephosphorylated by PP1 during progression not identified
3. 2022 High

   To test whether the PP1-inhibitory function has a genetic requirement in vivo, the P. berghei orthologue was shown to complex with and inhibit PbPP1 across stages and to be required for mosquito-stage oocyst development.

   Evidence Co-immunoprecipitation, phosphatase activity assay, and conditional genetic depletion with oocyst phenotype analysis, in P. berghei

   PMID:35920043

   Open questions at the time

   • Whether the P. falciparum orthologue has the same oocyst/transmission requirement not directly tested
   • Mechanism linking PP1 inhibition to oocyst maturation unresolved
   • Essentiality in asexual blood stages not defined
4. 2022 Medium

   To map the regulatory output of the complex, interactome and phosphoproteomic profiling identified Inhibitor 3 (I3) as a complex member whose phosphorylation is controlled by the PP1-LRR1 module.

   Evidence Interactome mass spectrometry and phospho-proteomics on PbLRR1-depleted parasites, in P. berghei

   PMID:35920043

   Open questions at the time

   • Functional consequence of I3 hypophosphorylation not directly tested
   • Whether I3 phosphorylation change is direct or indirect not established
   • Kinase(s) opposing PP1 on I3 not identified

• How PfLRR1-mediated PP1 inhibition is regulated during the parasite cell cycle and which parasite substrates are governed by the PfLRR1/PfPP1/I3 network in the human malaria parasite remain open.
• No PfLRR1 loss-of-function phenotype in P. falciparum
• No structural characterization of the complex
• Physiological substrates and cell cycle timing of PP1 inhibition unresolved