Structural basis for surface activation of the classical complement cascade by the short pentraxin C-reactive protein
Proceedings of the National Academy of Sciences, vol. 121, pp. e2404542121
Abstract
Human C-reactive protein (CRP) is a pentameric complex involved in immune defense and regulation of autoimmunity. CRP is also a therapeutic target, with both administration and depletion of serum CRP being pursued as a possible treatment for autoimmune and cardiovascular diseases, among others. CRP binds to phosphocholine (PC) moieties on membranes to activate the complement system via the C1 complex, but it is unknown how CRP, or any pentraxin, binds to C1. Here, we present a cryoelectron tomography (cryoET)-derived structure of CRP bound to PC ligands and the C1 complex. To gain control of CRP binding, a synthetic mimotope of PC was synthesized and used to decorate cell-mimetic liposome surfaces. Structure-guided mutagenesis of CRP yielded a fully active complex able to bind PC-coated liposomes that was ideal for cryoET and subtomogram averaging. In contrast to antibodies, which form Fc-mediated hexameric platforms to bind and activate the C1 complex, CRP formed rectangular platforms assembled from four laterally associated CRP pentamers that bind only four of the six available globular C1 head groups. Potential residues mediating lateral association of CRP were identified from interactions between unit cells in existing crystal structures, which rationalized previously unexplained mutagenesis data regarding CRP-mediated complement activation. The structure also enabled interpretation of existing biochemical data regarding interactions mediating C1 binding and identified additional residues for further mutagenesis studies. These structural data therefore provide a possible mechanism for regulation of complement by CRP, which limits complement progression and has consequences for how the innate immune system influences autoimmunity.
Authors 10
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Leiden University Medical Center
Affiliation as printed
Department of Cell and Chemical Biology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
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Affiliation as printed
Leiden Institute of Chemistry, Gorlaeus Laboratory, Leiden University, 2333 CC Leiden, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Cell and Chemical Biology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Cell and Chemical Biology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Cell and Chemical Biology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Cell and Chemical Biology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Immunology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Immunology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
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Affiliation as printed
Leiden Institute of Chemistry, Gorlaeus Laboratory, Leiden University, 2333 CC Leiden, The Netherlands
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Leiden University Medical Center · University of Bristol
Affiliation as printed
Department of Cell and Chemical Biology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
School of Biochemistry, University of Bristol, Bristol BS8 1TD, United Kingdom
Cited by 26 stored of 26
Cited by patents worldwide 2 (Lens.org)
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