PXD059888-1

PXD059888 is an original dataset announced via ProteomeXchange.

Title	Structural Insights into Complement Inhibition: Visualizing Distinct Binding Modes of C4b-binding Protein Complexes with C4b and SAP
Description	C4b-binding protein (C4BP) is an innate immune inhibitor found in serum. Human C4BP adopts spider-like higher-order structures (HOS) formed by disulfide-linked C4BPα and C4BPβ chains that non-covalently bind vitamin K-dependent protein S (ProS). These spider-like structures can form even larger complexes as C4BP interacts with other, mostly complement-related, proteins. The complement inhibitory role of C4BP is primarily mediated through its interaction with C4b. C4BP also binds with high affinity to serum amyloid P component (SAP), a pentraxin family member associated with amyloidosis conditions. Here, we structurally and compositionally characterize C4BP interactions with these two natively occurring binders. To achieve this, we combine mass photometry, high-speed atomic force microscopy, and cross-linking mass spectrometry. By integrating the results, we reveal two distinct binding modes of C4BP when bound to C4b or SAP. Given the spider-like assembly of C4BP, C4b interacts with the N-terminal region of a single C4BPα leg, enabling multiple C4b molecules to bind to the C4BP HOS. Conversely, SAP engages with the entire spider-like HOS: the C4BPα-C4BPβ oligomerization core binds to the B-face of SAP, and the C4BPα legs wrap around it.
HostingRepository	PRIDE
AnnounceDate	2025-08-07
AnnouncementXML	Submission_2025-08-07_03:56:37.226.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Tereza Kadavá
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2025-01-16 10:45:45	ID requested
⏵ 1	2025-08-07 03:56:37	announced

10.1016/j.mcpro.2025.101046;

Kadav, á T, Strasser J, Marefat M, Yin VC, Preiner J, Trouw LA, Heck AJR, Structural Insights Into Complement Inhibition: Visualizing Distinct Binding Modes of C4b-Binding Protein Complexes With C4b and SAP. Mol Cell Proteomics, 24(9):101046(2025) [pubmed]

submitter keyword: mass photometry, complement regulation, high-speed atomic force microscopy, serum amyloid P component., C4b-binding protein, C4b,cross-linking mass spectrometry

Albert J.R.
contact affiliation	Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, University of Utrecht
contact email	a.j.r.heck@uu.nl
lab head
Tereza Kadavá
contact affiliation	Utrecht University, Biomolecular Mass Spectrometry and Proteomics
contact email	t.kadava@uu.nl
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/08/PXD059888

PRIDE project URI

• PRIDE
  1. PXD059888
     1. Label: PRIDE project
     2. Name: Structural Insights into Complement Inhibition: Visualizing Distinct Binding Modes of C4b-binding Protein Complexes with C4b and SAP