PTRAMP, CSS and Ripr form a conserved complex required for merozoite invasion of Plasmodium species into erythrocytes

Benjamin A Seager1,2, Pailene S Lim1,2, Xiao Xiao1,2

  • 1The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.

Nature Communications
|January 26, 2026
PubMed

Insights

Malaria parasites use the PTRAMP-CSS-Ripr (PCR) complex to invade red blood cells. Antibodies targeting this conserved complex show potential for broad-acting malaria vaccines.

Area of Science:

  • Parasitology
  • Structural Biology
  • Immunology

Background:

  • Erythrocyte invasion by Plasmodium is crucial for malaria pathogenesis.
  • The Plasmodium falciparum Rh5 Invasion Complex (PCRCR) mediates erythrocyte binding via basigin.
  • Orthologs of PTRAMP, CSS, and Ripr are conserved across the Plasmodium genus.

Purpose of the Study:

  • To investigate conserved features of the PTRAMP-CSS-Ripr (PCR) complex across different Plasmodium species.
  • To elucidate the structural basis of PCR complex formation and antibody recognition.
  • To assess the potential of the PCR complex as a target for multi-species malaria vaccines.

Main Methods:

  • Comparative analysis of PTRAMP, CSS, and Ripr orthologs from P. vivax and P. knowlesi.
  • Biochemical assays to determine complex formation and disulfide linkage.
  • Antibody cross-reactivity studies and epitope mapping using structural biology techniques (crystallography, Cryo-EM).

Main Results:

  • PTRAMP and CSS form a disulfide-linked heterodimer in P. vivax and P. knowlesi, similar to P. falciparum.
  • The PTRAMP-CSS-Ripr (PCR) complex is conserved, binding Ripr's C-terminal region across species.
  • Cross-reactive antibodies targeting the PvRipr C-terminal tail differentially inhibit invasion, revealing a key inhibitory epitope.

Conclusions:

  • The PTRAMP-CSS-Ripr (PCR) complex represents a conserved invasion scaffold in Plasmodium species.
  • Structural insights into the PCR complex and antibody interactions pave the way for rational vaccine design.
  • Targeting the conserved PCR complex holds promise for developing vaccines effective against multiple malaria-causing parasites.

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