Reticulocyte binding protein homologs explained

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]

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. The trimeric complex forms an elongated structure with RH5 and Ripr on distal ends and CyRPA in the middle.[3] 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.[4] Of the entire family of RHs, only RH5 appears to be essential for invasion and functions downstream of the other RHs during invasion.[5]

PfRH4 is known to bind complement receptor 1.[6]

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.[7] A much better crystal structure for an N-terminal receptor-binding domain (presumably the same as EBD) was published in 2014.[8]

Notes and References

  1. Iyer J, Grüner AC, Rénia L, Snounou G, Preiser PR . Invasion of host cells by malaria parasites: a tale of two protein families . Molecular Microbiology . 65 . 2 . 231–49 . July 2007 . 17630968 . 10.1111/j.1365-2958.2007.05791.x . free .
  2. Lopaticki S, Maier AG, Thompson J, Wilson DW, Tham WH, Triglia T, Gout A, Speed TP, Beeson JG, Healer J, Cowman AF . 6 . Reticulocyte and erythrocyte binding-like proteins function cooperatively in invasion of human erythrocytes by malaria parasites . Infection and Immunity . 79 . 3 . 1107–17 . March 2011 . 21149582 . 3067488 . 10.1128/IAI.01021-10 .
  3. Wong W, Huang R, Menant S, Hong C, Sandow JJ, Birkinshaw RW, Healer J, Hodder AN, Kanjee U, Tonkin CJ, Heckmann D, Soroka V, Søgaard TM, Jørgensen T, Duraisingh MT, Czabotar PE, de Jongh WA, Tham WH, Webb AI, Yu Z, Cowman AF . 6 . Structure of Plasmodium falciparum Rh5-CyRPA-Ripr invasion complex . Nature . 565 . 7737 . 118–121 . January 2019 . 30542156 . 10.1038/s41586-018-0779-6 . 54472333 .
  4. Ragotte RJ, Higgins MK, Draper SJ . The RH5-CyRPA-Ripr Complex as a Malaria Vaccine Target . Trends in Parasitology . 36 . 6 . 545–559 . June 2020 . 32359873 . 7246332 . 10.1016/j.pt.2020.04.003 .
  5. Cowman AF, Tonkin CJ, Tham WH, Duraisingh MT . The Molecular Basis of Erythrocyte Invasion by Malaria Parasites . Cell Host & Microbe . 22 . 2 . 232–245 . August 2017 . 28799908 . 10.1016/j.chom.2017.07.003 . free .
  6. Tham WH, Wilson DW, Lopaticki S, Schmidt CQ, Tetteh-Quarcoo PB, Barlow PN, Richard D, Corbin JE, Beeson JG, Cowman AF . 6 . 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 . October 2010 . 20855594 . 2951459 . 10.1073/pnas.1008151107 . 2010PNAS..10717327T . free .
  7. Grüber A, Gunalan K, Ramalingam JK, Manimekalai MS, Grüber G, Preiser PR . Structural characterization of the erythrocyte binding domain of the reticulocyte binding protein homologue family of Plasmodium yoelii . Infection and Immunity . 79 . 7 . 2880–8 . July 2011 . 21482683 . 3191949 . 10.1128/IAI.01326-10 .
  8. Wright KE, Hjerrild KA, Bartlett J, Douglas AD, Jin J, Brown RE, Illingworth JJ, Ashfield R, Clemmensen SB, de Jongh WA, Draper SJ, Higgins MK . 6 . Structure of malaria invasion protein RH5 with erythrocyte basigin and blocking antibodies . Nature . 515 . 7527 . 427–30 . November 2014 . 25132548 . 4240730 . 10.1038/nature13715 . 2014Natur.515..427W .

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