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Human CD59 is a receptor for the cholesterol-dependent cytolysin intermedilysin

Abstract

Cholesterol is believed to serve as the common receptor for the cholesterol-dependent cytolysins (CDCs). One member of this toxin family, Streptococcus intermedius intermedilysin (ILY), exhibits a narrow spectrum of cellular specificity that is seemingly inconsistent with this premise. We show here that ILY, via its domain 4 structure, binds to the glycosyl-phosphatidylinositol–linked membrane protein human CD59 (huCD59). CD59 is an inhibitor of the membrane attack complex of human complement. ILY specifically binds to huCD59 via residues that are the binding site for the C8α and C9 complement proteins. These studies provide a new model for the mechanism of cellular recognition by a CDC.

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Figure 1: Binding and cytolytic activity of ILY on human and rabbit erythrocytes.
Figure 2: ILY binds to CD59 on human erythrocytes.
Figure 3: Antibodies to huCD59 inhibit binding and lysis of huRBC by ILY.
Figure 4: Murine SV-T2 cells expressing huCD59 bind and are sensitive to ILY.
Figure 5: ILY does not bind the N-linked carbohydrate of CD59.
Figure 6: ILY binds residues 42–58 of huCD59.
Figure 7: Domain 4 of ILY contains the recognition site for huCD59.
Figure 8: A model for binding and pore formation by the CDCs.

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Acknowledgements

This work was supported by grants from the US National Institute of Allergy and Infectious Diseases (AI037657 and T32 AI07364), and from the US National Heart, Lung and Blood Institute (HL36061) The technical assistance of A. Marpoe and L. Bentsen was appreciated.

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Correspondence to Rodney K Tweten.

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Giddings, K., Zhao, J., Sims, P. et al. Human CD59 is a receptor for the cholesterol-dependent cytolysin intermedilysin. Nat Struct Mol Biol 11, 1173–1178 (2004). https://doi.org/10.1038/nsmb862

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