Structural basis for Duffy recognition by the malaria parasite Duffy-binding-like domain
Abstract
Molecular processes that govern pathogenic features of erythrocyte invasion and cytoadherence in malaria are reliant on Plasmodium-specific Duffy-binding-like domains (DBLs). These cysteine-rich modules recognize diverse host cell-surface receptors during pathogenesis. DBLs of parasite erythrocyte-binding proteins mediate invasion, and those from the antigenically variant P. falciparum erythrocyte membrane protein 1 (PfEMP1) have been implicated in cytoadherence. The simian and human malarial parasites, P. knowlesi and P. vivax, invade human erythrocytes exclusively through the host DARC receptor (Duffy antigen receptor for chemokines). Here we present the crystal structure of the P. knowlesi DBL domain (Pkalpha-DBL), which binds to DARC during invasion of human erythrocytes. Pkalpha-DBL retains the overall fold observed in DBLs from P. falciparum erythrocyte-binding antigen (EBA)-175 (ref. 4). Mapping the residues that have previously been implicated in binding highlights a fairly flat but exposed site for DARC recognition in subdomain 2 of Pkalpha-DBL; this is in sharp contrast to receptor recognition by EBA-175 (ref. 4). In Pkalpha-DBL, the residues that contact DARC and the clusters of residues under immune pressure map to opposite surfaces of the DBL, and suggest a possible mechanism for immune evasion by P. vivax. Our comparative structural analysis of Pkalpha-DBL and P. falciparum EBA-175 provides a framework for the understanding of malaria parasite DBLs, and may affe…
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- Authors
- Singh, S. K., Hora, R., Belrhali, H., Chitnis, C. E., & Sharma, A.
- Affiliations
- International Centre for Genetic Engineering and Biotechnology (IN)
- European Molecular Biology Laboratory (FR)
- Corresponding author
- Sharma, Amit
- Venue
- Nature
- Published
- 2005-12-21
- Volume
- 439
- Issue
- 7077
- Pages
- 741-744
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1979611404
- Cited by
- 247
- References
- 0
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 6 · 2023: 6 · 2022: 6 · 2021: 8 · 2020: 7 · 2019: 9 · 2018: 11 · 2017: 6 · 2016: 9 · 2015: 11 · 2014: 15 · 2013: 8 · 2012: 14
- FWCI
- 20.82
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Malaria Research and Control
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Structural Characterization
- Health Sciences › Medicine › Physiology › Erythrocyte Function and Pathophysiology
- Keywords
- Duffy binding-like domain, Plasmodium knowlesi, DARC, erythrocyte invasion, crystal structure, EBA-175, PfEMP1, cytoadherence, immune evasion, antigenic variation, Plasmodium, Plasmodium vivax
- MeSH terms
- Amino Acid Sequence, Animals, Binding Sites, Disulfides, Duffy Blood-Group System, Erythrocytes, Humans, Models, Molecular, Molecular Sequence Data, Plasmodium falciparum, Protein Binding, Structure-Activity Relationship, Plasmodium knowlesi, Protein Structure, Tertiary, Protein Folding, Crystallography, X-Ray
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