Merozoite surface protein
{{Infobox nonhuman protein
| Name = Merozoite Surface Protein-1
| image = Merozoite Surface Protein Pre and Post Invasion Diagram.jpg
| width =
| caption = 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.
| Organism = Plasmodium knowlesi
| TaxID = 5851
| Symbol = MSP1
| EntrezGene = 7320035
| HomoloGene =
| PDB = 1N1I
| RefSeqmRNA = XM_002258546.1
| RefSeqProtein = XP_002258582.1
| UniProt = Q9GSQ9
| ECnumber =
| Chromosome = 7
| EntrezChromosome = NC_011908.1
| GenLoc_start = 1262619
| GenLoc_end = 1269724
}}
Merozoite {{IPAc-en|ˌ|m|ɛ|r|ə|ˈ|z|oʊ|ˌ|aɪ|t}} surface proteins are both integral and peripheral membrane proteins found on the surface of a merozoite, an early life cycle stage of a protozoan.{{cite journal | vauthors = Kadekoppala M, Holder AA | title = Merozoite surface proteins of the malaria parasite: the MSP1 complex and the MSP7 family | journal = International Journal for Parasitology | volume = 40 | issue = 10 | pages = 1155–61 | date = August 2010 | pmid = 20451527 | doi = 10.1016/j.ijpara.2010.04.008 }} 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.{{cite journal | vauthors = Singh S, Chitnis CE | title = Molecular Signaling Involved in Entry and Exit of Malaria Parasites from Host Erythrocytes | journal = Cold Spring Harbor Perspectives in Medicine | volume = 7 | issue = 10 | date = October 2017 | pages = a026815 | pmid = 28507195 | pmc = 5629987 | doi = 10.1101/cshperspect.a026815 }} 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.{{cite journal | vauthors = Beeson JG, Drew DR, Boyle MJ, Feng G, Fowkes FJ, Richards JS | title = Merozoite surface proteins in red blood cell invasion, immunity and vaccines against malaria | journal = FEMS Microbiology Reviews | volume = 40 | issue = 3 | pages = 343–72 | date = May 2016 | pmid = 26833236 | pmc = 4852283 | doi = 10.1093/femsre/fuw001 }}
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. Merozoite surface proteins 1 and 2 (MSP-1 and MSP-2) are the most abundant (GPI)-anchored proteins on the surface of Plasmodium merozoites.
Function
MSP-1 is synthesized at the very beginning of schizogony, or asexual merozoite reproduction.{{cite journal | vauthors = Holder AA | title = The carboxy-terminus of merozoite surface protein 1: structure, specific antibodies and immunity to malaria | journal = Parasitology | volume = 136 | issue = 12 | pages = 1445–56 | date = October 2009 | pmid = 19627632 | doi = 10.1017/S0031182009990515 | s2cid = 23402929 }} 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.{{cn|date=May 2021}} 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.{{cite journal | vauthors = Blackman MJ, Heidrich HG, Donachie S, McBride JS, Holder AA | title = 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 | journal = The Journal of Experimental Medicine | volume = 172 | issue = 1 | pages = 379–82 | date = July 1990 | pmid = 1694225 | pmc = 2188181 | doi=10.1084/jem.172.1.379}} The exact role of MSP-119 remains unknown, but it currently serves as a marker for the formation of the food vacuole.
File:Merozoite Surface Protein-1 Segments from Sequence Processing.tif
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. 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.
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.{{cite journal | vauthors = Versiani FG, Almeida ME, Mariuba LA, Orlandi PP, Nogueira PA | title = N-terminal Plasmodium vivax merozoite surface protein-1, a potential subunit for malaria vivax vaccine | journal = Clinical & Developmental Immunology | volume = 2013 | pages = 965841 | date = 2013 | pmid = 24187566 | pmc = 3804292 | doi = 10.1155/2013/965841 | doi-access = free }} In addition to vaccines, researchers are developing drugs that bind to MSPs in order to disrupt merozoite replication.{{cite journal | vauthors = 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 | title = Macrolides rapidly inhibit red blood cell invasion by the human malaria parasite, Plasmodium falciparum | journal = BMC Biology | volume = 13 | pages = 52 | date = July 2015 | pmid = 26187647 | pmc = 4506589 | doi = 10.1186/s12915-015-0162-0 | doi-access = free }} 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.{{cite journal | vauthors = Fleck SL, Birdsall B, Babon J, Dluzewski AR, Martin SR, Morgan WD, Angov E, Kettleborough CA, Feeney J, Blackman MJ, Holder AA | title = Suramin and suramin analogues inhibit merozoite surface protein-1 secondary processing and erythrocyte invasion by the malaria parasite Plasmodium falciparum | journal = The Journal of Biological Chemistry | volume = 278 | issue = 48 | pages = 47670–7 | date = November 2003 | pmid = 13679371 | doi = 10.1074/jbc.M306603200 | doi-access = free }}
= 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.{{cite journal | vauthors = Miller LH, Roberts T, Shahabuddin M, McCutchan TF | title = Analysis of sequence diversity in the Plasmodium falciparum merozoite surface protein-1 (MSP-1) | journal = Molecular and Biochemical Parasitology | volume = 59 | issue = 1 | pages = 1–14 | date = May 1993 | pmid = 8515771 | doi=10.1016/0166-6851(93)90002-f}} 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.{{cite journal | vauthors = Ouattara A, Barry AE, Dutta S, Remarque EJ, Beeson JG, Plowe CV | title = Designing malaria vaccines to circumvent antigen variability | journal = Vaccine | volume = 33 | issue = 52 | pages = 7506–12 | date = December 2015 | pmid = 26475447 | pmc = 4731100 | doi = 10.1016/j.vaccine.2015.09.110 }} 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. 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.{{cite journal | vauthors = Soni R, Sharma D, Rai P, Sharma B, Bhatt TK | title = Signaling Strategies of Malaria Parasite for Its Survival, Proliferation, and Infection during Erythrocytic Stage | journal = Frontiers in Immunology | volume = 8 | pages = 349 | date = 2017-03-28 | pmid = 28400771 | pmc = 5368685 | doi = 10.3389/fimmu.2017.00349 | doi-access = free }} Also MSP3 is being studied as a vaccine antigen.{{cite journal |vauthors=Baumann A, Magris MM, Urbaez ML, Vivas-Martinez S, Durán R, Nieves T, Esen M, Mordmüller BG, Theisen M, Avilan L, Metzger WG |title=Naturally acquired immune responses to malaria vaccine candidate antigens MSP3 and GLURP in Guahibo and Piaroa indigenous communities of the Venezuelan Amazon |journal=Malar J |volume=11 |issue= |pages=46 |date=February 2012 |pmid=22335967 |pmc=3296639 |doi=10.1186/1475-2875-11-46 |doi-access=free }}