Three SIBLINGs (small integrin-binding ligand, N-linked glycoproteins) enhance factor H's cofactor activity enabling MCP-like cellular evasion of complement-mediated attack.
Previously we have shown that two members of the newly named SIBLING (small integrin-binding ligand, N-linked glycoproteins) family of proteins, bone sialoprotein, and osteopontin, bound first to a cell surface receptor and then to complement Factor H thereby blocking the lytic activity of the alternative pathway of complement. Another member of this family, dentin matrix protein 1, is shown in this paper to be very similar to osteopontin in that it can bind strongly to Factor H (K(a) approximately 1 nm) and block the lytic activity through either the vitronectin receptor (alpha(V)beta(3) integrin) or CD44. Binding of Factor H to SIBLING localized to the cells surface was demonstrated by fluorescence-activated cell sorting. Extensive overlapping fragment analyses suggests that both dentin matrix protein 1 and osteopontin interact with cell surface CD44 through their amino termini. Similar fragments of bone sialoprotein, like the intact protein, did not functionally interact with CD44. All three proteins are shown to act in conjunction with Factor I, a serum protease that, when complexed to appropriate cofactors, stops the lytic pathway by digesting the bound C3b in a series of proteolytic steps. These results show that at least three members of this family confer membrane cofactor protein-like activity (MCP or CD46) upon cells expressing RGD-binding integrins or CD44. The required order of the assembly of the complex suggests that this cofactor activity is limited to short diffusional distances.
Jain
Alka
A
Division of Geriatrics, Department of Medicine, Johns Hopkins University, Baltimore, Maryland 21224, USA.
Karadag
Abdullah
A
Fohr
Berthold
B
Fisher
Larry W
LW
Fedarko
Neal S
NS
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D003386:Brachyura; D002417:Cattle; D002460:Cell Line; D002469:Cell Separation; D002851:Chromatography, High Pressure Liquid; D017242:Complement Factor H / Q000737:chemistry* / Q000145:classification / Q000378:metabolism; D003165:Complement System Proteins / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005091:Exons; D016326:Extracellular Matrix Proteins; D005434:Flow Cytometry; D006801:Humans; D018960:Hyaluronan Receptors / Q000737:chemistry* / Q000145:classification / Q000378:metabolism; D007700:Kinetics; D008954:Models, Biological; D008969:Molecular Sequence Data; D053495:Osteopontin; D010455:Peptides / Q000737:chemistry; D010750:Phosphoproteins / Q000097:blood* / Q000737:chemistry* / Q000145:classification; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000378:metabolism; D012795:Sialoglycoproteins / Q000737:chemistry* / Q000145:classification
C493495:CFH protein, human; C513309:DMP1 protein, human; D016326:Extracellular Matrix Proteins; D018960:Hyaluronan Receptors; D010455:Peptides; D010750:Phosphoproteins; D011994:Recombinant Proteins; C506895:SPP1 protein, human; D012795:Sialoglycoproteins; C506897:Spp1 protein, rat; D053495:Osteopontin; D017242:Complement Factor H; D003165:Complement System Proteins