Structural basis for sialic acid-mediated self-recognition by complement factor H

Baerbel S. Blaum*, Jonathan P. Hannan, Andrew P. Herbert, David Kavanagh, Dusan Uhrin, Thilo Stehle

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

The serum protein complement factor H (FH) ensures downregulation of the complement alternative pathway, a branch of innate immunity, upon interaction with specific glycans on host cell surfaces. Using ligand-based NMR, we screened a comprehensive set of sialylated glycans for binding to FH and solved the crystal structure of a ternary complex formed by the two C-terminal domains of FH, a sialylated trisaccharide and the complement C3b thioester-containing domain. Key residues in the sialic acid binding site are conserved from mice to men, and residues linked to atypical hemolytic uremic syndrome cluster within this binding site, suggesting a possible role for sialic acid as a host marker also in other mammals and a critical role in human renal complement homeostasis. Unexpectedly, the FH sialic acid binding site is structurally homologous to the binding sites of two evolutionarily unrelated proteins. The crystal structure also advances our understanding of bacterial immune evasion strategies.

Original languageEnglish
Pages (from-to)77-82
Number of pages7
JournalNature Chemical Biology
Volume11
Early online date24 Nov 2014
DOIs
Publication statusPublished - Jan 2015

Keywords

  • HEMOLYTIC-UREMIC SYNDROME
  • POLYANION BINDING-SITE
  • ALTERNATIVE PATHWAY
  • STRUCTURAL BASIS
  • MACULAR DEGENERATION
  • NMR-SPECTROSCOPY
  • C3 CONVERTASE
  • ACTIVATION
  • PROTEINS
  • MEMBRANE

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