PP7

PP7 (PF3D7_1423300) is a calcium-regulated serine/threonine protein phosphatase of Plasmodium falciparum that functions within a calcium-signaling module governing early intra-erythrocytic development (PMID:15230980, PMID:39387582). The full-length enzyme is activated by Ca2+ through its EF-hand domains, and rapid, specific in vivo proteolytic processing generates a constitutively active catalytic core that is largely Ca2+-independent (PMID:15230980). PP7 physically associates with calmodulin and calcium-dependent protein kinase 1 (CDPK1), and is itself a high-confidence substrate of cAMP-dependent protein kinase (PKA), linking calcium and cAMP signaling; loss of PP7 alters phosphorylation of PKAc substrates, indicating a role in shaping the phosphoproteome (PMID:39387582). Conditional disruption shows PP7 is dispensable for erythrocyte invasion but essential immediately afterward, with PP7-null parasites arresting shortly after invasion and failing to transition to ameboid ring-stage forms (PMID:39387582). Beyond this calcium-signaling and ring-stage developmental role, no further substrate-level mechanistic detail has been characterized in the available corpus.

1. 2004 Medium

   Establishing how PP7 activity is controlled, this work showed the enzyme is a Ca2+-regulated phosphatase whose EF-hand domains are required for calcium stimulation and whose activity can be switched to a constitutive state by proteolysis.

   Evidence Biochemical activity assays on full-length and proteolytically processed forms plus in vivo processing assays in P. falciparum

   PMID:15230980

   Open questions at the time

   • identity of the processing protease not determined
   • physiological trigger and timing of processing in the parasite life cycle unknown
   • in vivo substrates of the active enzyme not identified
2. 2008 Low

   Genome-wide phosphatome cataloguing placed PP7 within the PPP family (PPEF/PP7 subfamily), fixing its identity as one of a small set of parasite phosphatases but adding no mechanistic function.

   Evidence Bioinformatic/phylogenetic analysis of the P. falciparum genome via PlasmoDB

   PMID:18793411

   Open questions at the time

   • computational classification only, no experimental data on PP7
   • no functional or cellular role assigned
   • no interacting partners identified
3. 2024 High

   Integrating genetics, interactomics, and phosphoproteomics defined PP7's cellular role and signaling context: it is essential for early ring-stage development, sits in a calcium-signaling module with calmodulin and CDPK1, and is a PKA substrate that regulates PKAc substrate phosphorylation.

   Evidence Conditional knockout with phenotypic imaging, Co-IP with calmodulin and CDPK1, mass-spectrometry phosphoproteomics, and Ca2+-dependent activity assay in P. falciparum

   PMID:39387582

   Open questions at the time

   • direct dephosphorylation substrates of PP7 not defined (altered phosphosites may be indirect)
   • mechanism coupling PKA phosphorylation of PP7 to its phosphatase activity unresolved
   • molecular basis of the post-invasion arrest and ameboid transition failure not established

• The direct substrate repertoire of PP7 and how its Ca2+/EF-hand regulation, proteolytic processing, and PKA phosphorylation are integrated to control ring-stage development remain unknown.
• no validated direct substrate of PP7
• no structural model of the full-length versus processed enzyme
• interplay between processing, Ca2+ activation, and PKA phosphorylation uncharacterized