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The structure of serum resistance-associated protein and its implications for human African trypanosomiasis

DOI: 10.1038/s41564-017-0085-3 DOI Help

Authors: Sebastian Zoll (University of Oxford) , Harriet Lane-serff (University of Oxford) , Shahid Mehmood (University of Oxford) , Jonathan Schneider (University of Oxford) , Carol V. Robinson (University of Oxford) , Mark Carrington (University of Cambridge) , Matthew K. Higgins (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Microbiology , VOL 75

State: Published (Approved)
Published: January 2018
Diamond Proposal Number(s): 12346

Abstract: Only two trypanosome subspecies are able to cause human African trypanosomiasis. To establish an infection in human blood, they must overcome the innate immune system by resisting the toxic effects of trypanolytic factor 1 and trypanolytic factor 2 (refs. 1,2). These lipoprotein complexes contain an active, pore-forming component, apolipoprotein L1 (ApoL1), that causes trypanosome cell death3. One of the two human-infective subspecies, Trypanosoma brucei rhodesiense, differs from non-infective trypanosomes solely by the presence of the serum resistance-associated protein, which binds directly to ApoL1 and blocks its pore-forming capacity3,4,5. Since this interaction is the single critical event that renders T. b. rhodesiense human- infective, detailed structural information that allows identification of binding determinants is crucial to understand immune escape by the parasite. Here, we present the structure of serum resistance-associated protein and reveal the adaptations that occurred as it diverged from other trypanosome surface molecules to neutralize ApoL1. We also present our mapping of residues important for ApoL1 binding, giving molecular insight into this interaction at the heart of human sleeping sickness.

Journal Keywords: Parasite immune evasion; X-ray crystallography

Subject Areas: Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography