Structural basis for sialic acid-mediated self-recognition by complement factor H.
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.
Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany.
Bärbel S
BS
Blaum
Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, USA.
Jonathan P
JP
Hannan
The School of Chemistry, University of Edinburgh, Scotland, UK.
Andrew P
AP
Herbert
Institute of Genetic Medicine, International Centre for Life, Newcastle upon Tyne, UK.
David
D
Kavanagh
The School of Chemistry, University of Edinburgh, Scotland, UK.
Dušan
D
Uhrín
1] Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany. [2] Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Thilo
T
Stehle
D000818:Animals; D001665:Binding Sites; D002240:Carbohydrate Sequence; D003179:Complement C3b / Q000378:metabolism; D017242:Complement Factor H / Q000737:chemistry* / Q000378:metabolism; D003170:Complement Pathway, Alternative / Q000187:drug effects; D017124:Conserved Sequence; D006461:Hemolysis / Q000187:drug effects; D006463:Hemolytic-Uremic Syndrome / Q000235:genetics; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019158:N-Acetylneuraminic Acid / Q000737:chemistry* / Q000378:metabolism; D011134:Polysaccharides / Q000494:pharmacology; D012756:Sheep
D011134:Polysaccharides; D003179:Complement C3b; D017242:Complement Factor H; D019158:N-Acetylneuraminic Acid