CD59 is also highly expressed in B-cell lymphomas, contributing to immune evasion and protection from antibody-based therapeutics that activate complement 5, 6. Without it, MAC pores formed on red blood cells result in rupture, causing chronic hemolysis and immune-related neuropathies 4. CD59 is the only membrane-bound inhibitor of MAC on human cells and is the last line of defense against activation of the complement terminal pathway 3. A critical regulator of MAC is CD59, a GPI-anchored cell surface receptor. While a potent weapon of innate immune defense, MAC assembled on human cells has devastating consequences for disease pathologies 1, 2. The membrane attack complex (MAC) is a human immune pore that ruptures lipid bilayers to kill cells. We combine our structural data with cellular assays and molecular dynamics simulations to explain how the membrane environment impacts the dual roles of CD59 in controlling pore formation of MAC, and as a target of bacterial virulence factors which hijack CD59 to lyse human cells. Preventing insertion of C9 restricts structural transitions of subsequent monomers and indirectly halts MAC polymerization. While bound to C8, CD59 deflects the cascading C9 β-hairpins, rerouting their trajectory into the membrane. We discover that in both complexes, CD59 binds the pore-forming β-hairpins of C8 to form an intermolecular β-sheet that prevents membrane perforation. We present cryo-electron microscopy structures of two inhibited MAC precursors known as C5b8 and C5b9. Here we show how the receptor binds complement proteins C8 and C9 at the membrane to prevent insertion and polymerization of membrane attack complex (MAC) pores. CD59 is an abundant immuno-regulatory receptor that protects human cells from damage during complement activation.
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