MSP7

MSP7 (PF3D7_1335100) is a peripheral merozoite surface protein of Plasmodium that assembles with the MSP1 precursor to form part of the MSP1 surface complex and contributes to efficient erythrocyte invasion during the asexual blood stage (PMID:17097159, PMID:18820076). It is synthesized as a ~351-aa precursor in schizonts and undergoes sequential proteolytic maturation: a brefeldin A-sensitive primary cleavage in a post-Golgi compartment generates N-terminal MSP7(20) and C-terminal MSP7(33), with MSP7(33) remaining bound to full-length MSP1, followed by a surface secondary cleavage yielding MSP7(22) (PMID:11551634, PMID:17097159). This surface maturation is carried out by the subtilisin-like protease PfSUB1, which directly processes MSP7 within the MSP1/6/7 complex prior to egress; blocking PfSUB1 leaves unprocessed MSP7 on the merozoite surface and reduces invasion (PMID:19214190, PMID:21220481). MSP7 binds MSP1 directly and independently of MSP6, attaching to the shed p83, p30, and p38 subunits but not the GPI-anchored MSP1-42/19 region, defining it as a peripherally attached component of one of several distinct MSP1 complexes that engage the erythrocyte surface (PMID:16940297, PMID:29760216). The mature complex, including MSP7, is shed at the tight junction during invasion (PMID:24218484). Genetic disruption of msp7 is not lethal but impairs invasion without perturbing MSP1 expression or processing, and in P. berghei attenuates blood-stage growth and virulence in vivo (PMID:18820076, PMID:15339842, PMID:21980474); among the MSP7 gene family, only PF3D7_1335100 produces a detectable growth/invasion phenotype on deletion (PMID:20472690). Beyond its merozoite-surface role, MSP7 binds human P-selectin via its N-terminus at the C-type lectin and EGF-like domains, blocking P-selectin engagement of its Sialyl-Lewis(X) ligand (PMID:26045295).

1. 2001 High

   Establishing MSP7 as a processed merozoite surface protein answered whether it is a stable structural protein or a transiently displayed, shed molecule, framing it as an invasion-associated surface antigen.

   Evidence Gene sequencing, immunoblot and mass spectrometry of P. falciparum merozoite surface proteins

   PMID:11551634

   Open questions at the time

   • Did not define the protease(s) responsible for processing
   • Did not establish a functional role in invasion
2. 2002 Medium

   Identifying MSP7 as a direct binding partner of the MSP1 N-terminal fragment addressed how MSP7 is displayed on the surface, showing it is recruited through direct association with MSP1.

   Evidence Yeast two-hybrid screen, in vitro binding, and immunofluorescence co-localization in P. yoelii

   PMID:12477792

   Open questions at the time

   • Yeast two-hybrid is indirect and shown in P. yoelii
   • Did not map which MSP1 subunits bind MSP7
3. 2004 High

   Knocking out msp7 in P. berghei tested whether the protein is essential and revealed it is dispensable for viability but contributes to blood-stage growth and erythrocyte tropism.

   Evidence Targeted gene disruption with in vivo mouse infection and parasitemia monitoring in P. berghei

   PMID:15339842

   Open questions at the time

   • Mechanism linking MSP7 loss to reticulocyte preference unresolved
   • P. berghei phenotype not yet confirmed in a human-infective species
4. 2006 High

   Dissecting the biosynthetic pathway and mapping the MSP1 binding sites resolved where, when, and how MSP7 is processed and assembled onto MSP1.

   Evidence Pulse-chase labeling with inhibitor dissection, plus in vitro reconstitution with recombinant MSP1/MSP6/MSP7 and biophysical sizing in P. falciparum

   PMID:16940297 PMID:17097159

   Open questions at the time

   • The brefeldin A-sensitive primary protease was not identified
   • Functional consequence of multi-site binding not tested
5. 2007 Low

   Peptide binding assays probed whether MSP7 itself contacts the erythrocyte, indicating direct receptor engagement, but by a low-resolution surrogate approach.

   Evidence Synthetic high-activity binding peptides, RBC binding with enzymatic treatment, and invasion inhibition in P. falciparum

   PMID:17944453

   Open questions at the time

   • Peptide binding does not recapitulate full-length protein interactions
   • The 52 kDa erythrocyte partner was not molecularly identified
6. 2008 High

   A clean P. falciparum knockout tested whether the invasion role is conserved in a human parasite and showed MSP7 loss impairs invasion without disrupting other surface protein processing.

   Evidence Targeted disruption in P. falciparum D10 with Southern, immunoblot, immunofluorescence and invasion assays

   PMID:18820076

   Open questions at the time

   • Did not identify the molecular step of invasion that MSP7 assists
   • No evidence for compensatory alternative invasion pathway
7. 2009 High

   Identifying PfSUB1 as the maturase resolved the enzyme responsible for MSP7 surface processing and linked that processing to invasion competence.

   Evidence PfSUB1 inhibition with immunoblot of surface proteins and invasion assays in P. falciparum

   PMID:19214190 PMID:21220481

   Open questions at the time

   • Does not distinguish the invasion contribution of MSP7 processing from that of co-substrates MSP1/MSP6
   • Primary post-Golgi protease remains unidentified
8. 2010 Medium

   Live imaging and family-wide knockouts localized MSP7 shedding to the tight junction and established PF3D7_1335100 as the functionally dominant family member.

   Evidence Time-lapse invasion imaging with immunofluorescence, plus individual disruption of all MSP7-family genes with growth/invasion assays in P. falciparum

   PMID:20472690 PMID:24218484

   Open questions at the time

   • Molecular trigger of shedding not defined
   • Why MSRP paralogs are phenotypically silent in blood stages is unexplained
9. 2011 Medium

   In vivo P. berghei studies established that MSP7 loss reduces disease severity and virulence, extending its role beyond invasion efficiency.

   Evidence Single and double (msp7/plasmepsin-4) knockouts with mouse and rat infection, hematology, and cerebral malaria assessment in P. berghei

   PMID:21980474 PMID:22355558

   Open questions at the time

   • In the double mutant, MSP7's contribution cannot be fully separated from plasmepsin-4
   • Molecular basis of the virulence effect is unknown
10. 2016 Medium

    Extracellular interaction screening uncovered a host-directed activity, showing MSP7 binds human P-selectin and blocks its carbohydrate ligand, and confirmed reciprocal, erythrocyte-engaging MSP1 complexes.

    Evidence AVEXIS screen, domain-mapping binding and competition assays for P-selectin; Co-IP, recombinant binding and erythrocyte binding for MSP1 complexes in P. falciparum

    PMID:26045295 PMID:26823464

    Open questions at the time

    • Physiological relevance of the P-selectin interaction during infection not demonstrated in vivo
    • Single lab, single-species biochemical validation
11. 2018 Medium

    Compositional analysis defined the broader MSP1 complex membership, placing MSP7 alongside MSP3, MSP6, and MSP9 with direct MSP1 binding confirmed.

    Evidence Anti-MSP3 immunoprecipitation with mass spectrometry, ELISA and surface plasmon resonance in P. falciparum

    PMID:29760216

    Open questions at the time

    • Stoichiometry and spatial arrangement of the multi-protein complex not resolved
    • Single lab

• The identity of the brefeldin A-sensitive primary protease and the precise molecular step of invasion that MSP7 facilitates remain unresolved.
• Primary post-Golgi protease that generates MSP7(33)/MSP7(20) unidentified
• Direct erythrocyte receptor for full-length MSP7 not defined
• In vivo relevance of MSP7-P-selectin binding untested