Abstract
The complement system is essential for immune defence against infection and modulation of proinflammatory responses. Activation of the terminal pathway of complement triggers formation of the membrane attack complex (MAC), a multi-protein pore that punctures membranes. Recent advances in structural biology, specifically cryo-electron microscopy (cryoEM), have provided atomic resolution snapshots along the pore formation pathway. These structures have revealed dramatic conformational rearrangements that enable assembly and membrane rupture. Here we review the structural basis for MAC formation and show how soluble proteins transition into a giant β-barrel pore. We also discuss regulatory complexes of the terminal pathway and their impact on structure-guided drug discovery of complement therapeutics.
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Acknowledgements
This work is supported by a CRUK Career Establishment Award (C26409/A16099) to D.B.; J.K.B. is supported by an EPSRC Doctoral Prize Fellowship and funded by an EPSRC Doctoral Training Program grant (EP/L015498/1); T.B.V. is funded by a BBSRC Doctoral Training Program grant (BB/M011178/1); E.W.T and D.B. are supported by a NIHR Imperial Biomedical Research Centre (BRC) Award (RDF01) and an EPSRC Impact Acceleration Account (EP/R511547/1). Figs were created with BioRender.com and rendered using UCSF Chimera (Pettersen et al. 2004) or PyMOL (The PyMOL Molecular Graphics System, Version 2.0 Schrödinger, LLC).
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Bickel, J.K., Voisin, T.B., Tate, E.W., Bubeck, D. (2021). How Structures of Complement Complexes Guide Therapeutic Design. In: Harris, J.R., Marles-Wright, J. (eds) Macromolecular Protein Complexes III: Structure and Function. Subcellular Biochemistry, vol 96. Springer, Cham. https://doi.org/10.1007/978-3-030-58971-4_7
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