8OVB

Human Complement C3b in complex with Trypanosoma brucei ISG65.

Summary for 8OVB

• Entry DOI: 10.2210/pdb8ovb/pdb
• EMDB information: 17209 17219 17220 17221 17273
• Descriptor: Complement C3f fragment, Complement C3, ISG65 G (3 entities in total)
• Functional Keywords: complement system, parasite virulence, trypanosome surface protein, host-pathogen complex, immune system
• Biological source: Trypanosoma brucei brucei; More
• Total number of polymer chains: 3
• Total formula weight: 207824.53

Authors

Cook, A.D.,Higgins, M.K. (deposition date: 2023-04-25, release date: 2024-02-14, Last modification date: 2024-10-23)

Primary citation

Cook, A.D.,Carrington, M.,Higgins, M.K.
Molecular mechanism of complement inhibition by the trypanosome receptor ISG65.
Elife, 12:-, 2024

PubMed Abstract: African trypanosomes replicate within infected mammals where they are exposed to the complement system. This system centres around complement C3, which is present in a soluble form in serum but becomes covalently deposited onto the surfaces of pathogens after proteolytic cleavage to C3b. Membrane-associated C3b triggers different complement-mediated effectors which promote pathogen clearance. To counter complement-mediated clearance, African trypanosomes have a cell surface receptor, ISG65, which binds to C3b and which decreases the rate of trypanosome clearance in an infection model. However, the mechanism by which ISG65 reduces C3b function has not been determined. We reveal through cryogenic electron microscopy that ISG65 has two distinct binding sites for C3b, only one of which is available in C3 and C3d. We show that ISG65 does not block the formation of C3b or the function of the C3 convertase which catalyses the surface deposition of C3b. However, we show that ISG65 forms a specific conjugate with C3b, perhaps acting as a decoy. ISG65 also occludes the binding sites for complement receptors 2 and 3, which may disrupt recruitment of immune cells, including B cells, phagocytes, and granulocytes. This suggests that ISG65 protects trypanosomes by combining multiple approaches to dampen the complement cascade.

PubMed: 38655765
DOI: 10.7554/eLife.88960

Experimental method

ELECTRON MICROSCOPY (3.4 Å)