Multiple ligand binding sites on domain seven of human complement factor H.
Foreign particles and damaged host cells can activate the complement system leading to their destruction by the host defense system. Factor H (fH) plays a vital role in restricting complement activation on host cells through interactions with polyanions such as heparin, while allowing activation to proceed on foreign surfaces. Complement activation by damaged host cells is also down regulated by fH, which is localized to injured areas through interactions with C-reactive protein (CRP). A number of pathogens have developed mechanisms by which they can also bind fH and thus exploit its protective properties. One such organism is Group A Streptococcus (GAS) which mediates fH binding via its surface expressed M-protein. fH consists of 20 conserved short consensus repeat (SCR) units and mutagenesis studies indicate that the seventh repeat is responsible for interactions with heparin, CRP and M-protein. We recently performed molecular modelling of fH SCR 7 and identified a cluster of positively charged residues on one face of the domain. By alanine replacement mutagenesis, we demonstrated that these residues are involved in heparin, CRP and M protein binding, which indicates that there is a common site within fH SCR 7 responsible for multiple ligand recognition.
Giannakis
E
E
Department of Microbiology and Infectious Diseases, Flinders Medical Centre, Bedford Park, South Australia 5042.
Male
D A
DA
Ormsby
R J
RJ
Mold
C
C
Jokiranta
T S
TS
Ranganathan
S
S
Gordon
D L
DL
D000595:Amino Acid Sequence; D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; D001426:Bacterial Proteins / Q000276:immunology; D001665:Binding Sites; D002097:C-Reactive Protein / Q000276:immunology; D002352:Carrier Proteins / Q000276:immunology; D003167:Complement Activation; D017242:Complement Factor H / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006493:Heparin / Q000737:chemistry; D006801:Humans; D066298:In Vitro Techniques; D007239:Infections / Q000209:etiology; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019158:N-Acetylneuraminic Acid / Q000276:immunology; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D013297:Streptococcus pyogenes / Q000276:immunology
D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; D001426:Bacterial Proteins; C493495:CFH protein, human; D002352:Carrier Proteins; D008024:Ligands; C014689:streptococcal M protein; D017242:Complement Factor H; D006493:Heparin; D002097:C-Reactive Protein; D019158:N-Acetylneuraminic Acid