Processing of Plasmodium falciparum Merozoite Surface Protein MSP1 Activates a Spectrin-Binding Function Enabling Parasite Egress from RBCs

Summary The malaria parasite Plasmodium falciparum replicates within erythrocytes, producing progeny merozoites that are released from infected cells via a poorly understood process called egress. The most abundant merozoite surface protein, MSP1, is synthesized as a large precursor that undergoes proteolytic maturation by the parasite protease SUB1 just prior to egress. The function of MSP1 and its processing are unknown. Here we show that SUB1-mediated processing of MSP1 is important for parasite viability. Processing modifies the secondary structure of MSP1 and activates its capacity to bind spectrin, a molecular scaffold protein that is the major component of the host erythrocyte cytoskeleton. Parasites expressing an inefficiently processed MSP1 mutant show delayed egress, and merozoites lacking surface-bound MSP1 display a severe egress defect. Our results indicate that interactions between SUB1-processed merozoite surface MSP1 and the spectrin network of the erythrocyte cytoskeleton facilitate host erythrocyte rupture to enable parasite egress.

• Publication year

  2015

• Venue

  Cell Host and Microbe

• Publication date

  2015-10-14

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1016/j.chom.2015.09.007PMID 26468747PMCID 4608996
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Merozoite surface protein 1 recognition of host glycophorin A mediates malaria parasite invasion of red blood cells.

  2015cited by this paper
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  2015cited by this paper
• Plasmodium falciparum SERA5 plays a non-enzymatic role in the malarial asexual blood-stage lifecycle

  2015cited by this paper
• The Merozoite Surface Protein 1 Complex Is a Platform for Binding to Human Erythrocytes by Plasmodium falciparum*

  2014cited by this paper
• Quantitation of malaria parasite-erythrocyte cell-cell interactions using optical tweezers.

  2014cited by this paper
• A Library of Functional Recombinant Cell-surface and Secreted P. falciparum Merozoite Proteins*

  2013cited by this paper
• Robust inducible Cre recombinase activity in the human malaria parasite Plasmodium falciparum enables efficient gene deletion within a single asexual erythrocytic growth cycle

  2013cited by this paper
• Recent insights into apicomplexan parasite egress provide new views to a kill.

  2013cited by this paper
• An automated live imaging platform for studying merozoite egress-invasion in malaria cultures.

  2013cited by this paper
• Malaria Parasite cGMP-dependent Protein Kinase Regulates Blood Stage Merozoite Secretory Organelle Discharge and Egress

  2013cited by this paper
• Proteomic analysis of Plasmodium falciparum schizonts reveals heparin-binding merozoite proteins.

  2013cited by this paper
• Proteolytic Activation of the Essential Parasitophorous Vacuole Cysteine Protease SERA6 Accompanies Malaria Parasite Egress from Its Host Erythrocyte

  2012cited by this paper
• Plasmodium subtilisin-like protease 1 (SUB1): Insights into the active-site structure, specificity and function of a pan-malaria drug target

  2012cited by this paper
• The cell biology of disease: The cellular and molecular basis for malaria parasite invasion of the human red blood cell

  2012cited by this paper
• A novel mechanism for egress of malarial parasites from red blood cells.

  2011cited by this paper
• Global Identification of Multiple Substrates for Plasmodium falciparum SUB1, an Essential Malarial Processing Protease

  2011cited by this paper
• An Erythrocyte Cytoskeleton-Binding Motif in Exported Plasmodium falciparum Proteins

  2011cited by this paper
• Biophysics of Malarial Parasite Exit from Infected Erythrocytes

  2011cited by this paper
• Super-resolution dissection of coordinated events during malaria parasite invasion of the human erythrocyte.

  2011influential reference
• New stages in the program of malaria parasite egress imaged in normal and sickle erythrocytes.

  2010cited by this paper
• Regulated maturation of malaria merozoite surface protein-1 is essential for parasite growth

  2010cited by this paper
• Control of erythrocyte membrane-skeletal cohesion by the spectrin-membrane linkage.

  2010cited by this paper
• Interactions with heparin-like molecules during erythrocyte invasion by Plasmodium falciparum merozoites.

  2010cited by this paper
• Apicomplexan Parasites Co-Opt Host Calpains to Facilitate Their Escape from Infected Cells

  2009cited by this paper
• Irreversible effect of cysteine protease inhibitors on the release of malaria parasites from infected erythrocytes

  2009influential reference
• The carboxy-terminus of merozoite surface protein 1: structure, specific antibodies and immunity to malaria

  2009cited by this paper
• The Malaria Parasite Cyclic GMP-Dependent Protein Kinase Plays a Central Role in Blood-Stage Schizogony

  2009cited by this paper
• Morphology and kinetics of the three distinct phases of red blood cell invasion by Plasmodium falciparum merozoites.

  2009cited by this paper
• Clonal conditional mutagenesis in malaria parasites.

  2009cited by this paper
• A multifunctional serine protease primes the malaria parasite for red blood cell invasion

  2009cited by this paper
• An Inhibitory Antibody Blocks Interactions between Components of the Malarial Invasion Machinery

  2009cited by this paper
• A regulatable transgene expression system for cultured Plasmodium falciparum parasites

  2008cited by this paper
• Spectrin domains lose cooperativity in forced unfolding.

  2007cited by this paper
• Subcellular discharge of a serine protease mediates release of invasive malaria parasites from host erythrocytes.

  2007cited by this paper
• Tropomyosin modulates erythrocyte membrane stability.

  2007cited by this paper
• Intramembrane proteolysis mediates shedding of a key adhesin during erythrocyte invasion by the malaria parasite

  2006cited by this paper
• Interactions between Merozoite Surface Proteins 1, 6, and 7 of the Malaria Parasite Plasmodium falciparum*

  2006cited by this paper
• Mammalian alpha I-spectrin is a neofunctionalized polypeptide adapted to small highly deformable erythrocytes.

  2006influential reference
• Molecular Identification of a Malaria Merozoite Surface Sheddase

  2005cited by this paper
• Computation and Analysis of Protein Circular Dichroism Spectra

  2004influential reference
• A Co-ligand Complex Anchors Plasmodium falciparum Merozoites to the Erythrocyte Invasion Receptor Band 3*

  2004cited by this paper
• A Common Cross-species Function for the Double Epidermal Growth Factor-like Modules of the Highly Divergent Plasmodium Surface Proteins MSP-1 and MSP-8*

  2004cited by this paper
• Band 3 is a host receptor binding merozoite surface protein 1 during the Plasmodium falciparum invasion of erythrocytes

  2003cited by this paper
• Plasmodium falciparum merozoite surface protein 1.

  2003cited by this paper
• The Merozoite Surface Protein 1 Complex of Human Malaria Parasite Plasmodium falciparum

  2003cited by this paper
• Expression of Recombinant Plasmodium falciparumSubtilisin-like Protease-1 in Insect Cells

  2002cited by this paper
• Structural and biochemical characterization of a fluorogenic rhodamine-labeled malarial protease substrate.

  2002cited by this paper
• The merozoite surface protein 6 gene codes for a 36 kDa protein associated with the Plasmodium falciparum merozoite surface protein-1 complex.

  2001cited by this paper
• The 22 kDa component of the protein complex on the surface of Plasmodium falciparum merozoites is derived from a larger precursor, merozoite surface protein 7.

  2001cited by this paper
• Functional conservation of the malaria vaccine antigen MSP-119across distantly related Plasmodium species

  2000cited by this paper
• Vaccine candidate MSP-1 from Plasmodium falciparum: a redesigned 4917 bp polynucleotide enables synthesis and isolation of full-length protein from Escherichia coli and mammalian cells.

  1999influential reference
• A Subtilisin-like Protein in Secretory Organelles of Plasmodium falciparum Merozoites*

  1998cited by this paper
• Saccharide anions as inhibitors of the malaria parasite

  1997cited by this paper
• In vitro folding of inclusion body proteins

  1996cited by this paper
• Purification of Plasmodium falciparum merozoites for analysis of the processing of merozoite surface protein-1.

  1994cited by this paper
• N-terminal amino acid sequence of the Plasmodium falciparum merozoite surface protein-1 polypeptides.

  1994cited by this paper
• A conserved parasite serine protease processes the Plasmodium falciparum merozoite surface protein-1.

  1993cited by this paper
• A conserved region of the MSP‐1 surface protein of Plasmodium falciparum contains a recognition sequence for erythrocyte spectrin.

  1993cited by this paper
• A monoclonal antibody capable of blocking the binding of Pf200 (MSA-1) to human erythrocytes and inhibiting the invasion of Plasmodium falciparum merozoites into human erythrocytes.

  1993cited by this paper
• Effect of different fractions of heparin on Plasmodium falciparum merozoite invasion of red blood cells in vitro.

  1992cited by this paper
• Membrane-associated proteases process Plasmodium falciparum merozoite surface antigen-1 (MSA1) to fragment gp41.

  1992cited by this paper
• Processing of the Plasmodium falciparum major merozoite surface protein-1: identification of a 33-kilodalton secondary processing product which is shed prior to erythrocyte invasion.

  1991cited by this paper
• The N-terminal amino acid sequences of the Plasmodium falciparum (FCB1) merozoite surface antigens of 42 and 36 kilodalton, both derived from the 185-195-kilodalton precursor.

  1989cited by this paper
• Processing of the precursor to the major merozoite surface antigens of Plasmodium falciparum

  1987cited by this paper
• Fragments of the polymorphic Mr 185,000 glycoprotein from the surface of isolated Plasmodium falciparum merozoites form an antigenic complex.

  1987influential reference
• Primary structure of the precursor to the three major surface antigens of Plasmodium falciparum merozoites

  1985cited by this paper
• Biosynthesis and processing of a Plasmodium falciparum schizont antigen recognized by immune serum and a monoclonal antibody

  1982cited by this paper
• On the size of the active site in proteases. I. Papain.

  1967cited by this paper

• Chromatin state dynamics during the Plasmodium falciparum intraerythrocytic development cycle

  2026cites this paper
• Plasmodium blood stage development requires the chromatin remodeller Snf2L

  2025cites this paper
• In Silico Design Of Antimalarial Drug From Catharanthus Roseus (G. Don) Alkaloid Molecules against AMA1 Protein

  2025cites this paper
• Chromatin state dynamics during the Plasmodium falciparum intraerythrocytic development cycle

  2025cites this paper
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  2025cites this paper
• In-Host Modeling and Analysis of Plasmodium Falciparum Infection in Humans and Impacts on Immune System

  2025cites this paper
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  2025cites this paper
• Hexosamine biosynthesis disruption impairs GPI production and arrests Plasmodium falciparum growth at schizont stages

  2025influential citation
• Erythrocyte binding peptides: a story in the search for a malaria vaccine

  2025cites this paper
• An abundant merozoite surface protein of Plasmodium falciparum modulates susceptibility to inhibitory antibodies

  2025influential citation
• Differential importance of MSP4 and MSP5 for infection of red blood cells between human infecting malaria parasites

  2025cites this paper
• Glycosylation in malaria parasites: what do we know?

  2024cites this paper
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  2024cites this paper
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  2022cites this paper
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  2022cites this paper
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  2021influential citation
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  2021cites this paper
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  2021cites this paper
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  2021cites this paper
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  2021cites this paper
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  2021cites this paper
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  2021cites this paper
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  2020cites this paper
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  2020cites this paper
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  2020cites this paper
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  2020cites this paper
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  2020cites this paper
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  2020cites this paper
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  2020cites this paper
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  2020cites this paper
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  2020influential citation
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  2020cites this paper
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  2020cites this paper
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  2020cites this paper
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  2020cites this paper
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  2020cites this paper
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  2020cites this paper
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  2020cites this paper
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  2020cites this paper
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  2020cites this paper
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  2020cites this paper
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  2020cites this paper
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  2020cites this paper
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  2019cites this paper
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  2019cites this paper
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  2019cites this paper
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  2019cites this paper
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  2019cites this paper