Merozoite surface protein

Merozoite /ˌmɛrəˈzoʊˌaɪt/ surface proteins are both integral and peripheral membrane proteins found on the surface of a merozoite, an early life cycle stage of a protozoan.[1] Merozoite surface proteins, or MSPs, are important in understanding malaria, a disease caused by protozoans of the genus Plasmodium. During the asexual blood stage of its life cycle, the malaria parasite enters red blood cells to replicate itself, causing the classic symptoms of malaria.[3] These surface protein complexes are involved in many interactions of the parasite with red blood cells and are therefore an important topic of study for scientists aiming to combat malaria.[4]

Merozoite Surface Protein-1
The MSP-1 complex is attached to the merozoite cell membrane via GPI-anchoring, indicated by the staggered lines penetrating the cell membrane. After red blood cell invasion, the majority of the MSP-1 complex is shed, leaving MSP-119 behind.[1]
Identifiers
OrganismPlasmodium knowlesi
SymbolMSP1
Alt. symbolsPKH_072850 [2]
Entrez7320035
PDB1N1I
RefSeq (mRNA)XM_002258546.1
RefSeq (Prot)XP_002258582.1
UniProtQ9GSQ9
Other data
Chromosome7: 1.26 - 1.27 Mb

Forms

The most common form of MSPs are anchored to the merozoite surface with glycophosphatidylinositol, a short glycolipid often used for protein anchoring. Additional forms include integral membrane proteins and peripherally associated proteins, which are found to a lesser extent than glycophosphatidylinositol anchored proteins, or (GPI)-anchored proteins, on the merozoite surface.[4] Merozoite surface proteins 1 and 2 (MSP-1 & MSP-2) are the most abundant (GPI)-anchored proteins on the surface of Plasmodium merozoites.[4]

Function

MSP-1 is synthesized at the very beginning of schizogony, or asexual merozoite reproduction.[5] The merozoite first attaches to a red blood cell using its MSP-1 complex. The MSP-1 complex targets spectrin, a complex on the internal surface of the cell membrane of a red blood cell. The majority of the MSP-1 complex is shed upon entry into the red blood cell, but a small portion of the C-terminus, called MSP-119, is conserved.[6] The exact role of MSP-119 remains unknown, but it currently serves as a marker for the formation of the food vacuole.[1]

The relative size and location of each segment present on the MSP-1 complex is shown above. SS represents the signal sequence, which is a short sequence present on the N-terminus of new proteins. GA represents the GPI anchor, which is located at the C-terminus of the protein.[7]

The function of the MSP-2 complex is not concrete, but current research suggests it has a role in red blood cell invasion due to its degradation shortly after invasion.[4] MSP- 3, 6, 7 and 9 are peripheral membrane proteins that have been shown to form a complex with MSP-1, but the functions of these proteins are largely unknown.[4]

Clinical significance

Due to their prevalence on the Plasmodium surface, MSPs have been a key target for vaccine development. Anti-malarial vaccines have been developed to target the merozoite at different stages in its life cycle. Vaccines that target the merozoite in its asexual erythrocytic stage utilize merozoite surface proteins, particularly MSP-1.[8] In addition to vaccines, researchers are developing drugs that bind to MSPs in order to disrupt merozoite replication.[9] Suramin, a drug used to treat African sleeping sickness, has shown moderate success with binding to MSP-1 and its derivatives such as MSP-119 to inhibit red blood cell invasion.[10]

Challenges

The challenge faced when developing vaccines is the complexity and variation of these proteins. In merozoites of the same genus and species, the sequences encoding proteins such as MSP-1 vary depending on the region they are found.[11] For example, the Combination B vaccine utilizes antigens of MSP-1 and MSP-2 but has limited efficacy based primarily on the MSP-2 alleles used.[12] In an attempt to increase the efficiency of vaccines produced, constant regions such as MSP-119 which remain on the surface of the Plasmodium after the merozoite stage are becoming a key focus for vaccine studies.[4] Additionally, synthetic glycophosphatidylinositol (GPI) molecules are candidates since they elicit a strong immune response while simultaneously remaining relatively consistent in structure over various malarial strains.[13]

References
  1. Kadekoppala M, Holder AA (August 2010). "Merozoite surface proteins of the malaria parasite: the MSP1 complex and the MSP7 family". International Journal for Parasitology. 40 (10): 1155–61. doi:10.1016/j.ijpara.2010.04.008. PMID 20451527.
  2. "PKH_072850 merozoite surface protein 1, MSP-1 [ Plasmodium knowlesi strain H ]". Entrez Gene. National Center for Biotechnology Information (NCBI), U.S. National Library of Medicine. Retrieved 2018-11-26.
  3. Singh S, Chitnis CE (October 2017). "Molecular Signaling Involved in Entry and Exit of Malaria Parasites from Host Erythrocytes". Cold Spring Harbor Perspectives in Medicine. 7 (10). doi:10.1101/cshperspect.a026815. PMC 5629987. PMID 28507195.
  4. Beeson JG, Drew DR, Boyle MJ, Feng G, Fowkes FJ, Richards JS (May 2016). "Merozoite surface proteins in red blood cell invasion, immunity and vaccines against malaria". FEMS Microbiology Reviews. 40 (3): 343–72. doi:10.1093/femsre/fuw001. PMC 4852283. PMID 26833236.
  5. Holder AA (October 2009). "The carboxy-terminus of merozoite surface protein 1: structure, specific antibodies and immunity to malaria". Parasitology. 136 (12): 1445–56. doi:10.1017/S0031182009990515. PMID 19627632.
  6. Blackman MJ, Heidrich HG, Donachie S, McBride JS, Holder AA (July 1990). "A single fragment of a malaria merozoite surface protein remains on the parasite during red cell invasion and is the target of invasion-inhibiting antibodies". The Journal of Experimental Medicine. 172 (1): 379–82. doi:10.1084/jem.172.1.379. PMC 2188181. PMID 1694225.
  7. Woehlbier U, Epp C, Hackett F, Blackman MJ, Bujard H (March 2010). "Antibodies against multiple merozoite surface antigens of the human malaria parasite Plasmodium falciparum inhibit parasite maturation and red blood cell invasion". Malaria Journal. 9 (1): 77. doi:10.1186/1475-2875-9-77. PMC 2847572. PMID 20298576.
  8. Versiani FG, Almeida ME, Mariuba LA, Orlandi PP, Nogueira PA (2013). "N-terminal Plasmodium vivax merozoite surface protein-1, a potential subunit for malaria vivax vaccine". Clinical & Developmental Immunology. 2013: 965841. doi:10.1155/2013/965841. PMC 3804292. PMID 24187566.
  9. Wilson DW, Goodman CD, Sleebs BE, Weiss GE, de Jong NW, Angrisano F, Langer C, Baum J, Crabb BS, Gilson PR, McFadden GI, Beeson JG (July 2015). "Macrolides rapidly inhibit red blood cell invasion by the human malaria parasite, Plasmodium falciparum". BMC Biology. 13: 52. doi:10.1186/s12915-015-0162-0. PMC 4506589. PMID 26187647.
  10. Fleck SL, Birdsall B, Babon J, Dluzewski AR, Martin SR, Morgan WD, Angov E, Kettleborough CA, Feeney J, Blackman MJ, Holder AA (November 2003). "Suramin and suramin analogues inhibit merozoite surface protein-1 secondary processing and erythrocyte invasion by the malaria parasite Plasmodium falciparum". The Journal of Biological Chemistry. 278 (48): 47670–7. doi:10.1074/jbc.M306603200. PMID 13679371.
  11. Miller LH, Roberts T, Shahabuddin M, McCutchan TF (May 1993). "Analysis of sequence diversity in the Plasmodium falciparum merozoite surface protein-1 (MSP-1)". Molecular and Biochemical Parasitology. 59 (1): 1–14. doi:10.1016/0166-6851(93)90002-f. PMID 8515771.
  12. Ouattara A, Barry AE, Dutta S, Remarque EJ, Beeson JG, Plowe CV (December 2015). "Designing malaria vaccines to circumvent antigen variability". Vaccine. 33 (52): 7506–12. doi:10.1016/j.vaccine.2015.09.110. PMC 4731100. PMID 26475447.
  13. Soni R, Sharma D, Rai P, Sharma B, Bhatt TK (2017-03-28). "Signaling Strategies of Malaria Parasite for Its Survival, Proliferation, and Infection during Erythrocytic Stage". Frontiers in Immunology. 8: 349. doi:10.3389/fimmu.2017.00349. PMC 5368685. PMID 28400771.
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