title: A polymorphism in the type one complement receptor (CR1) involves an additional cysteine within the C3b/C4b binding domain that inhibits ligand binding.
abstract: The type one complement receptor (CR1) contains a variable number of binding domains for C3b and C4b, formed through a nearly identical set of repeating units known as short consensus repeats (SCRs). Each SCR contains four cysteines that, by forming two disulfide bonds, impart a conformation critical for function. In this study, we identified a CR1 single nucleotide polymorphism (1597C>T) that results in an additional cysteine (483R>C) in SCR 8 of the N-terminal C3b/C4b binding domain, and occurring sporadically in corresponding SCRs of other repeated C3b/C4b binding domains. The normal carrier frequency for 483-C was 6.3% in 175 African Americans, and 2.4% in 153 Caucasians. In expression constructs containing one C3b/C4b binding domain, the 483-C residue reduced binding to C3b, C3bi, and C4b by over 80% (each p<0.0001), versus the wildtype construct. Full-length CR1 from 483-C carriers also exhibited reduced binding to C3b and C4b, although the effect was influenced by the total number of binding domains present. Race-matched comparisons between SLE patients (86 African Americans, 228 Caucasians) and the normal cohort showed that 483-C carrier status alone is not a risk factor for SLE or lupus nephritis. The physiological role of this polymorphism remains to be determined.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, The Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210, United States. Dan.Birmingham@osumc.edu <Dan.Birmingham@osumc.edu>
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Birmingham
authors.forename: Fawzi
authors.initials: F
authors.lastname: Irshaid
authors.forename: Katherine F
authors.initials: KF
authors.lastname: Gavit
authors.forename: Haikady N
authors.initials: HN
authors.lastname: Nagaraja
authors.forename: C Yung
authors.initials: CY
authors.lastname: Yu
authors.forename: Brad H
authors.initials: BH
authors.lastname: Rovin
authors.forename: Lee A
authors.initials: LA
authors.lastname: Hebert
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D003179:Complement C3b / Q000276:immunology*; D015935:Complement C4b / Q000276:immunology*; D003545:Cysteine / Q000235:genetics*; D003596:Cytosine; D005787:Gene Frequency; D006801:Humans; D008024:Ligands; D008180:Lupus Erythematosus, Systemic / Q000235:genetics; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011951:Receptors, Complement / Q000737:chemistry / Q000235:genetics*; D020449:Repetitive Sequences, Amino Acid; D013941:Thymine
chemical_list: D008024:Ligands; D011951:Receptors, Complement; D003179:Complement C3b; D015935:Complement C4b; D003596:Cytosine; D003545:Cysteine; D013941:Thymine