Arranged Sevenfold: Structural Insights into the C-Terminal Oligomerization Domain of Human C4b-Binding Protein

Abstract

CitationArranged sevenfold: structural insights into the C-terminal oligomerization domain of human C4b-binding protein. HighlightsCore crystal structure of a major modulator of complement system Human C4BP core complex reveals heptameric ring structure 7 disulfide bonds and 3 layers of electrostatic interactions provide high stability Molecular modeling provides insights into the structure of heterooligomeric isoforms Running titleCrystal structure of human C4BP core complex -2 - AbstractThe complement system as major part of innate immunity is the first line of defense against invading microorganisms. Orchestrated by more than 60 proteins, its major task is to discriminate between host cells and pathogens and to initiate immune response. Additional recognition of necrotic or apoptotic cells demand a fine-tune regulation of this powerful system. C4b-binding protein (C4BP) is the major inhibitor of the classical complement and lectin pathway. The crystal structure of the human C4BP oligomerization domain in its 7 isoform and molecular simulations provide first structural insights of C4BP oligomerization. The heptameric core structure is stabilized by intermolecular disulfide bonds.In addition, thermal shift assays indicate that layers of electrostatic interactions mainly contribute to the extraordinary thermodynamic stability of the complex. These findings make C4BP a promising scaffold for multivalent ligand display with applications in immunology and biological chemistry.

Molecular assembly of the aerolysin pore reveals a swirling membrane-insertion mechanism

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