5mi0

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A thermally stabilised version of Plasmodium falciparum RH5A thermally stabilised version of Plasmodium falciparum RH5

Structural highlights

5mi0 is a 3 chain structure with sequence from Mus musculus and Plasmodium falciparum. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.35Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

RH5_PLAF7 Essential for the invasion of host erythrocytes by blood stage merozoites (PubMed:18827878, PubMed:19000690, PubMed:22080952, PubMed:25296023, PubMed:25583518, PubMed:27374406, PubMed:28186186, PubMed:28409866, PubMed:31204103). By binding P113 at the surface of the merozoite and human BSG/basigin on the erythrocyte membrane, leads to the establishment of a tight junction between the merozoite and host erythrocyte membranes (PubMed:22080952, PubMed:25296023, PubMed:25583518, PubMed:27374406, PubMed:28186186). In addition, the interaction with BSG results in BSG dimerization which triggers an increase in intracellular Ca(2+) in the erythrocyte (PubMed:27374406, PubMed:28409866). This essential step leads to a rearrangement of the erythrocyte cytoskeleton required for the merozoite invasion (PubMed:28409866).[1] [2] [3] [4] [5] [6] [7] [8] [9]

Publication Abstract from PubMed

Many promising vaccine candidates from pathogenic viruses, bacteria, and parasites are unstable and cannot be produced cheaply for clinical use. For instance, Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) is essential for erythrocyte invasion, is highly conserved among field isolates, and elicits antibodies that neutralize in vitro and protect in an animal model, making it a leading malaria vaccine candidate. However, functional RH5 is only expressible in eukaryotic systems and exhibits moderate temperature tolerance, limiting its usefulness in hot and low-income countries where malaria prevails. Current approaches to immunogen stabilization involve iterative application of rational or semirational design, random mutagenesis, and biochemical characterization. Typically, each round of optimization yields minor improvement in stability, and multiple rounds are required. In contrast, we developed a one-step design strategy using phylogenetic analysis and Rosetta atomistic calculations to design PfRH5 variants with improved packing and surface polarity. To demonstrate the robustness of this approach, we tested three PfRH5 designs, all of which showed improved stability relative to wild type. The best, bearing 18 mutations relative to PfRH5, expressed in a folded form in bacteria at >1 mg of protein per L of culture, and had 10-15 degrees C higher thermal tolerance than wild type, while also retaining ligand binding and immunogenic properties indistinguishable from wild type, proving its value as an immunogen for a future generation of vaccines against the malaria blood stage. We envision that this efficient computational stability design methodology will also be used to enhance the biophysical properties of other recalcitrant vaccine candidates from emerging pathogens.

One-step design of a stable variant of the malaria invasion protein RH5 for use as a vaccine immunogen.,Campeotto I, Goldenzweig A, Davey J, Barfod L, Marshall JM, Silk SE, Wright KE, Draper SJ, Higgins MK, Fleishman SJ Proc Natl Acad Sci U S A. 2017 Jan 17. pii: 201616903. doi:, 10.1073/pnas.1616903114. PMID:28096331[10]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Rodriguez M, Lustigman S, Montero E, Oksov Y, Lobo CA. PfRH5: a novel reticulocyte-binding family homolog of plasmodium falciparum that binds to the erythrocyte, and an investigation of its receptor. PLoS One. 2008 Oct 1;3(10):e3300. PMID:18827878 doi:10.1371/journal.pone.0003300
  2. ↑ Baum J, Chen L, Healer J, Lopaticki S, Boyle M, Triglia T, Ehlgen F, Ralph SA, Beeson JG, Cowman AF. Reticulocyte-binding protein homologue 5 invasion of human erythrocytes by Plasmodium falciparum. Int J Parasitol. 2009 Feb;39(3):371-80. PMID:19000690 doi:10.1016/j.ijpara.2008.10.006
  3. ↑ Crosnier C, Bustamante LY, Bartholdson SJ, Bei AK, Theron M, Uchikawa M, Mboup S, Ndir O, Kwiatkowski DP, Duraisingh MT, Rayner JC, Wright GJ. Basigin is a receptor essential for erythrocyte invasion by Plasmodium falciparum. Nature. 2011 Nov 9;480(7378):534-7. PMID:22080952 doi:10.1038/nature10606
  4. ↑ Chen L, Xu Y, Healer J, Thompson JK, Smith BJ, Lawrence MC, Cowman AF. Crystal structure of PfRh5, an essential P. falciparum ligand for invasion of human erythrocytes. Elife. 2014 Oct 8;3:e04187. PMID:25296023 doi:10.7554/eLife.04187
  5. ↑ Reddy KS, Amlabu E, Pandey AK, Mitra P, Chauhan VS, Gaur D. Multiprotein complex between the GPI-anchored CyRPA with PfRH5 and PfRipr is crucial for Plasmodium falciparum erythrocyte invasion. Proc Natl Acad Sci U S A. 2015 Jan 27;112(4):1179-84. PMID:25583518 doi:10.1073/pnas.1415466112
  6. ↑ Volz JC, Yap A, Sisquella X, Thompson JK, Lim NT, Whitehead LW, Chen L, Lampe M, Tham WH, Wilson D, Nebl T, Marapana D, Triglia T, Wong W, Rogers KL, Cowman AF. Essential Role of the PfRh5/PfRipr/CyRPA Complex during Plasmodium falciparum Invasion of Erythrocytes. Cell Host Microbe. 2016 Jul 13;20(1):60-71. PMID:27374406 doi:10.1016/j.chom.2016.06.004
  7. ↑ Galaway F, Drought LG, Fala M, Cross N, Kemp AC, Rayner JC, Wright GJ. P113 is a merozoite surface protein that binds the N terminus of Plasmodium falciparum RH5. Nat Commun. 2017 Feb 10;8:14333. PMID:28186186 doi:10.1038/ncomms14333
  8. ↑ Aniweh Y, Gao X, Hao P, Meng W, Lai SK, Gunalan K, Chu TT, Sinha A, Lescar J, Chandramohanadas R, Li HY, Sze SK, Preiser PR. P. falciparum RH5-Basigin interaction induces changes in the cytoskeleton of the host RBC. Cell Microbiol. 2017 Sep;19(9). PMID:28409866 doi:10.1111/cmi.12747
  9. ↑ Alanine DGW, Quinkert D, Kumarasingha R, Mehmood S, Donnellan FR, Minkah NK, Dadonaite B, Diouf A, Galaway F, Silk SE, Jamwal A, Marshall JM, Miura K, Foquet L, Elias SC, Labbe GM, Douglas AD, Jin J, Payne RO, Illingworth JJ, Pattinson DJ, Pulido D, Williams BG, de Jongh WA, Wright GJ, Kappe SHI, Robinson CV, Long CA, Crabb BS, Gilson PR, Higgins MK, Draper SJ. Human Antibodies that Slow Erythrocyte Invasion Potentiate Malaria-Neutralizing Antibodies. Cell. 2019 Jun 13. pii: S0092-8674(19)30553-7. doi: 10.1016/j.cell.2019.05.025. PMID:31204103 doi:http://dx.doi.org/10.1016/j.cell.2019.05.025
  10. ↑ Campeotto I, Goldenzweig A, Davey J, Barfod L, Marshall JM, Silk SE, Wright KE, Draper SJ, Higgins MK, Fleishman SJ. One-step design of a stable variant of the malaria invasion protein RH5 for use as a vaccine immunogen. Proc Natl Acad Sci U S A. 2017 Jan 17. pii: 201616903. doi:, 10.1073/pnas.1616903114. PMID:28096331 doi:http://dx.doi.org/10.1073/pnas.1616903114

5mi0, resolution 2.35Å

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