Reticulocyte binding protein homologs

Reticulocyte binding protein homologs (RHs) are a superfamily of proteins found in Plasmodium responsible for cell invasion. Together with the family of erythrocyte binding-like proteins (EBLs) they make up the two families of invasion proteins universal to Plasmodium.[1] The two families function cooperatively.[2]

Plasmodium falciparum reticulocyte-binding protein homolog 5 (RH5), coiled-coil domain
Identifiers
SymbolRf5
PfamPF18515
InterProIPR041668

This family is named after the reticulocyte binding proteins in P. vivax, a parasite that only infects reticulocytes (immature red blood cells) expressing the Duffy antigen. Homologs have since been identified in P. yoelii and P. reichenowi.[1]

A P. falciparum protein complex called PfRH5-PfCyRPA-PfRipr (RCR) is known to bind basigin via the tip of RH5.[3] The trimeric complex forms an elongated structure with RH5 and Ripr on distal ends and CyRPA in the middle.[4] The RCR complex has been identified as a promising malaria vaccine target with each individual component capable of inducing strain transcending immunity in in vitro assays of parasite growth.[5] Of the entire family of RHs, only RH5 appears to be essential for invasion and functions downstream of the other RHs during invasion.[6]

PfRH4 is known to bind complement receptor 1.[7]

RHs do not express any significant sequence feature for specific domains, except for a set of transmembrane helices at the C-terminal. From experimentation on partial proteins, RHs are known to contain enterocyte-binding and nucleotide-sensing domains (EBD and NBD) that may partially overlap. The structure of the EBD has been experimentally observed in 2011 by small angle X-ray scattering.[8] A much better crystal structure for an N-terminal receptor-binding domain (presumably the same as EBD) was published in 2014.[3]

References
  1. Iyer J, Grüner AC, Rénia L, Snounou G, Preiser PR (July 2007). "Invasion of host cells by malaria parasites: a tale of two protein families". Molecular Microbiology. 65 (2): 231–49. doi:10.1111/j.1365-2958.2007.05791.x. PMID 17630968.
  2. Lopaticki S, Maier AG, Thompson J, Wilson DW, Tham WH, Triglia T, et al. (March 2011). "Reticulocyte and erythrocyte binding-like proteins function cooperatively in invasion of human erythrocytes by malaria parasites". Infection and Immunity. 79 (3): 1107–17. doi:10.1128/IAI.01021-10. PMC 3067488. PMID 21149582.
  3. Wright KE, Hjerrild KA, Bartlett J, Douglas AD, Jin J, Brown RE, et al. (November 2014). "Structure of malaria invasion protein RH5 with erythrocyte basigin and blocking antibodies". Nature. 515 (7527): 427–30. Bibcode:2014Natur.515..427W. doi:10.1038/nature13715. PMC 4240730. PMID 25132548.
  4. Wong W, Huang R, Menant S, Hong C, Sandow JJ, Birkinshaw RW, et al. (January 2019). "Structure of Plasmodium falciparum Rh5-CyRPA-Ripr invasion complex". Nature. 565 (7737): 118–121. doi:10.1038/s41586-018-0779-6. PMID 30542156. S2CID 54472333.
  5. Ragotte RJ, Higgins MK, Draper SJ (June 2020). "The RH5-CyRPA-Ripr Complex as a Malaria Vaccine Target". Trends in Parasitology. 36 (6): 545–559. doi:10.1016/j.pt.2020.04.003. PMC 7246332. PMID 32359873.
  6. Cowman AF, Tonkin CJ, Tham WH, Duraisingh MT (August 2017). "The Molecular Basis of Erythrocyte Invasion by Malaria Parasites". Cell Host & Microbe. 22 (2): 232–245. doi:10.1016/j.chom.2017.07.003. PMID 28799908.
  7. Tham WH, Wilson DW, Lopaticki S, Schmidt CQ, Tetteh-Quarcoo PB, Barlow PN, et al. (October 2010). "Complement receptor 1 is the host erythrocyte receptor for Plasmodium falciparum PfRh4 invasion ligand". Proceedings of the National Academy of Sciences of the United States of America. 107 (40): 17327–32. Bibcode:2010PNAS..10717327T. doi:10.1073/pnas.1008151107. PMC 2951459. PMID 20855594.
  8. Grüber A, Gunalan K, Ramalingam JK, Manimekalai MS, Grüber G, Preiser PR (July 2011). "Structural characterization of the erythrocyte binding domain of the reticulocyte binding protein homologue family of Plasmodium yoelii". Infection and Immunity. 79 (7): 2880–8. doi:10.1128/IAI.01326-10. PMC 3191949. PMID 21482683.
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