Structural basis for membrane attack complex inhibition by CD59

Couves, Emma C.; Gardner, Scott; Voisin, Tomas B.; J, Bickel; Stansfeld, Phillip J.; Tate, Edward W.; Bubeck, Doryen

doi:10.1038/s41467-023-36441-z

“…This cleaves complement factor C5, generating C5b, which recruits factors C6 and C7 to cause membrane association. Factors C8 and C9 can then bind to C5b7 on the pathogen surface, leading to the formation of a pore which mediates cell death ( Couves et al, 2023 ).…”

Section: Introductionmentioning

confidence: 99%

Molecular mechanism of complement inhibition by the trypanosome receptor ISG65

Cook

¹

,

Carrington

²

,

Higgins

³

2024

eLife

0

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African trypanosomes replicate within infected mammals where they are constantly exposed to the molecules of the complement system. This system centres around complement factor C3, which is present in a soluble form in serum but can become covalently deposited onto the surfaces of pathogens after proteolytic cleavage to C3b. Membrane-associated C3b triggers different complement-mediated effectors which promote pathogen clearance, including complement receptor-mediated stimulation of immune cells or recruitment of components of the pore-forming membrane attack complex. 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 had 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, ensuring that ISG65 preferentially binds to active C3b. 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 will 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.

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“…Although these bacterial toxins can still bind cholesterol-rich membranes, CD59 determines the species specificity for these virulence factors [ 9 ] and coordinates oligomerization necessary for structural transitions en route to the final pore [ 12 ]. While there is extensive structural information on how CD59 engages MAC proteins [ 13 ] and CDCs [ 14 , 15 ], investigating the molecular interactions of GPI-anchored CD59 in a membrane environment will inform how CD59 satisfies its opposing roles in pore formation.…”

Section: Introductionmentioning

confidence: 99%

“…CD59 blocks MAC at the first instance of membrane perforation by binding C8α [ 4 , 27 ]. Recent cryo-electron microscopy (cryoEM) studies have shown how CD59 re-directs pore-forming residues of the C8α MACPF [ 13 ]. CD59 binds C8α through a C-terminal β-strand of its central β-sheet, catching the cascading transmembrane residues and templating the newly formed C8α β-hairpin.…”

Section: Introductionmentioning

confidence: 99%

Dynamics and Molecular Interactions of GPI-Anchored CD59

Voisin

¹

,

Couves

²

,

Tate

³

et al. 2023

Toxins

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CD59 is a GPI-anchored cell surface receptor that serves as a gatekeeper to controlling pore formation. It is the only membrane-bound inhibitor of the complement membrane attack complex (MAC), an immune pore that can damage human cells. While CD59 blocks MAC pores, the receptor is co-opted by bacterial pore-forming proteins to target human cells. Recent structures of CD59 in complexes with binding partners showed dramatic differences in the orientation of its ectodomain relative to the membrane. Here, we show how GPI-anchored CD59 can satisfy this diversity in binding modes. We present a PyLipID analysis of coarse-grain molecular dynamics simulations of a CD59-inhibited MAC to reveal residues of complement proteins (C6:Y285, C6:R407 C6:K412, C7:F224, C8β:F202, C8β:K326) that likely interact with lipids. Using modules of the MDAnalysis package to investigate atomistic simulations of GPI-anchored CD59, we discover properties of CD59 that encode the flexibility necessary to bind both complement proteins and bacterial virulence factors.

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“…This cleaves complement factor C5, generating C5b, which recruits factors C6 and C7 to cause membrane association. Factors C8 and C9 can then bind to C5b7 on the pathogen surface, leading to the formation of a pore which mediates cell death 18 .…”

Section: Introductionmentioning

confidence: 99%

Molecular mechanism of complement inhibition by the trypanosome receptor ISG65

Cook

¹

,

Carrington

²

,

Higgins

³

2023

Preprint

2

0

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African trypanosomes replicate within infected mammals where they are constantly exposed to the molecules of the complement system. This system centres around complement factor C3, which is present in a soluble form in serum but can become covalently deposited onto the surfaces of pathogens after proteolytic cleavage to C3b. Membrane-associated C3b triggers different complement-mediated effectors which promote pathogen clearance, including complement receptor-mediated stimulation of immune cells or recruitment of components of the pore-forming membrane attack complex. 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 had 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, ensuring that ISG65 preferentially binds to active C3b. 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 will 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.

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Structural basis for membrane attack complex inhibition by CD59

Cited by 20 publications

References 92 publications

Molecular mechanism of complement inhibition by the trypanosome receptor ISG65

Molecular mechanism of complement inhibition by the trypanosome receptor ISG65

Dynamics and Molecular Interactions of GPI-Anchored CD59

Molecular mechanism of complement inhibition by the trypanosome receptor ISG65

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