Dataset Information

Structural Insights into Complement Inhibition: Visualizing Distinct Binding Modes of C4b-binding Protein Complexes with C4b and SAP

ABSTRACT: 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood

SUBMITTER: Tereza Kadavá

LAB HEAD: Albert J.R.

PROVIDER: PXD059888 | Pride | 2025-08-07

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	20230301_EX1_UM8_kadav001_SA_EXT00_X_DSSO_1_DSSO.raw	Raw
	20230301_EX1_UM8_kadav001_SA_EXT00_X_DSSO_2_DSSO.raw	Raw
	20230301_EX1_UM8_kadav001_SA_EXT00_X_DSSO_3_DSSO.raw	Raw
	20230901_EX2_UM7_kadav001_SA_C4_BP_DSG1.raw	Raw
	20230901_EX2_UM7_kadav001_SA_C4_BP_DSG2.raw	Raw

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Publications

Structural Insights Into Complement Inhibition: Visualizing Distinct Binding Modes of C4b-Binding Protein Complexes With C4b and SAP.

Kadavá Tereza T Strasser Jürgen J Marefat Maryam M Yin Victor C VC Preiner Johannes J Trouw Leendert A LA Heck Albert J R AJR

Molecular & cellular proteomics : MCP 20250805 9

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 affini ...[more]

PMID: 40754140

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