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Structurally conserved erythrocyte-binding domain in Plasmodium provides a versatile scaffold for alternate receptor engagement

Gruszczyk, J., Lim, N.T.Y., Arnott, A., He, W.Q., Nguitragool, W., Roobsoong, W., Mok, Y.F., Murphy, J.M., Smith, K.R., Lee, S., Bahlo, M., Mueller, I., Barry, Alyssa and Tham, W.H. 2016, Structurally conserved erythrocyte-binding domain in Plasmodium provides a versatile scaffold for alternate receptor engagement, Proceedings of the National Academy of Sciences of the United States of America, vol. 113, no. 2, pp. E191-E200, doi: 10.1073/pnas.1516512113.

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Title Structurally conserved erythrocyte-binding domain in Plasmodium provides a versatile scaffold for alternate receptor engagement
Author(s) Gruszczyk, J.
Lim, N.T.Y.
Arnott, A.
He, W.Q.
Nguitragool, W.
Roobsoong, W.
Mok, Y.F.
Murphy, J.M.
Smith, K.R.
Lee, S.
Bahlo, M.
Mueller, I.
Barry, AlyssaORCID iD for Barry, Alyssa orcid.org/0000-0002-1189-2310
Tham, W.H.
Journal name Proceedings of the National Academy of Sciences of the United States of America
Volume number 113
Issue number 2
Start page E191
End page E200
Total pages 10
Publisher National Academy of Sciences
Place of publication Irvine, Calif.
Publication date 2016-01-12
ISSN 0027-8424
1091-6490
Keyword(s) Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
parasite invasion
X-ray crystallography
SAXS
reticulocyte binding protein
malaria
PROTEIN SECONDARY STRUCTURE
DUFFY-BLOOD-GROUP
INVASION
FALCIPARUM
VIVAX
ANTIBODIES
COMPLEX
PY235
PFRH5
DNA
Summary Understanding how malaria parasites gain entry into human red blood cells is essential for developing strategies to stop blood stage infection. Plasmodium vivax preferentially invades reticulocytes, which are immature red blood cells. The organism has two erythrocyte-binding protein families: namely, the Duffy-binding protein (PvDBP) and the reticulocyte-binding protein (PvRBP) families. Several members of the PvRBP family bind reticulocytes, specifically suggesting a role in mediating host cell selectivity of P. vivax. Here, we present, to our knowledge, the first high-resolution crystal structure of an erythrocyte-binding domain from PvRBP2a, solved at 2.12 Å resolution. The monomeric molecule consists of 10 α-helices and one short β-hairpin, and, although the structural fold is similar to that of PfRh5—the essential invasion ligand in Plasmodium falciparum—its surface properties are distinct and provide a possible mechanism for recognition of alternate receptors. Sequence alignments of the crystallized fragment of PvRBP2a with other PvRBPs highlight the conserved placement of disulfide bonds. PvRBP2a binds mature red blood cells through recognition of an erythrocyte receptor that is neuraminidase- and chymotrypsin-resistant but trypsin-sensitive. By examining the patterns of sequence diversity within field isolates, we have identified and mapped polymorphic residues to the PvRBP2a structure. Using mutagenesis, we have also defined the critical residues required for erythrocyte binding. Characterization of the structural features that govern functional erythrocyte binding for the PvRBP family provides a framework for generating new tools that block P. vivax blood stage infection.
Language eng
DOI 10.1073/pnas.1516512113
Indigenous content off
Field of Research 110704 Cellular Immunology
HERDC Research category C1 Refereed article in a scholarly journal
Free to Read? Yes
Persistent URL http://hdl.handle.net/10536/DRO/DU:30136660

Document type: Journal Article
Collections: Faculty of Health
School of Medicine
Open Access Collection
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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.