Higher-order structure and proteoforms of co-occurring C4b-binding protein assemblies in human serum.

Autor:	Kadavá T; Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, Padualaan 8, Utrecht, 3584 CH, the Netherlands.; Netherlands Proteomics Center, Padualaan 8, Utrecht, 3584 CH, the Netherlands., Hevler JF; Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, Padualaan 8, Utrecht, 3584 CH, the Netherlands.; Netherlands Proteomics Center, Padualaan 8, Utrecht, 3584 CH, the Netherlands., Kalaidopoulou Nteak S; Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, Padualaan 8, Utrecht, 3584 CH, the Netherlands.; Netherlands Proteomics Center, Padualaan 8, Utrecht, 3584 CH, the Netherlands., Yin VC; Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, Padualaan 8, Utrecht, 3584 CH, the Netherlands.; Netherlands Proteomics Center, Padualaan 8, Utrecht, 3584 CH, the Netherlands., Strasser J; University of Applied Sciences Upper Austria, 4020, Linz, Austria., Preiner J; University of Applied Sciences Upper Austria, 4020, Linz, Austria., Heck AJ; Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, Padualaan 8, Utrecht, 3584 CH, the Netherlands. a.j.r.heck@uu.nl.; Netherlands Proteomics Center, Padualaan 8, Utrecht, 3584 CH, the Netherlands. a.j.r.heck@uu.nl.
Jazyk:	angličtina
Zdroj:	The EMBO journal [EMBO J] 2024 Jul; Vol. 43 (14), pp. 3009-3026. Date of Electronic Publication: 2024 May 29.
DOI:	10.1038/s44318-024-00128-y
Abstrakt:	The complement is a conserved cascade that plays a central role in the innate immune system. To maintain a delicate equilibrium preventing excessive complement activation, complement inhibitors are essential. One of the major fluid-phase complement inhibitors is C4b-binding protein (C4BP). Human C4BP is a macromolecular glycoprotein composed of two distinct subunits, C4BPα and C4BPβ. These associate with vitamin K-dependent protein S (ProS) forming an ensemble of co-occurring higher-order structures. Here, we characterize these C4BP assemblies. We resolve and quantify isoforms of purified human serum C4BP using distinct single-particle detection techniques: charge detection mass spectrometry, and mass photometry accompanied by high-speed atomic force microscopy. Combining cross-linking mass spectrometry, glycoproteomics, and structural modeling, we report comprehensive glycoproteoform profiles and full-length structural models of the endogenous C4BP assemblies, expanding knowledge of this key complement inhibitor's structure and composition. Finally, we reveal that an increased C4BPα to C4BPβ ratio coincides with elevated C-reactive protein levels in patient plasma samples. This observation highlights C4BP isoform variation and affirms a distinct role of co-occurring C4BP assemblies upon acute phase inflammation. (© 2024. The Author(s).)
Databáze:	MEDLINE
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