Mapping of the C3d receptor (CR2)-binding site and a neoantigenic site in the C3d domain of the third component of complement.

Lambris, John D.; Ganu, Vishwas; Hirani, Shirish; Müller‐Eberhard, Hans J.

doi:10.1073/pnas.82.12.4235

Cited by 87 publications

(58 citation statements)

References 36 publications

(19 reference statements)

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“…An additional potential site of C3d for interaction with full-length CR2 could include the sequence segment Glu 228 -Asp-Pro-Gly-Lys-Gln-Leu-Tyr-Asn-ValGlu-Ala 239 , which is not located within the ionizable residue channel. This site was first proposed by peptide mapping studies (72) and was confirmed by surface plasmon resonance studies (36). The presence of this binding site was also supported by site-directed mutagenesis studies within this site, in which simultaneous multiple replacements resulted to ϳ20% reduction in binding ability relative to wild type (34).…”

Section: Length Of Cr2mentioning

confidence: 75%

The Electrostatic Nature of C3d-Complement Receptor 2 Association

Morikis

Lambris

2004

The Journal of Immunology

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The association of complement component C3d with B or T cell complement receptor 2 (CR2 or CD21) is a link between innate and adaptive immunity. It has been recognized in experimental studies that the C3d-CR2 association is pH- and ionic strength-dependent. This led us to perform electrostatic calculations to obtain a theoretical understanding of the mechanism of C3d-CR2 association. We used the crystallographic structures of human free C3d, free CR2 (short consensus repeat (SCR)1–2), and the C3d-CR2(SCR1–2) complex, and continuum solvent representation, to obtain a detailed atomic-level picture of the components of the two molecules that contribute to association. Based on the calculation of electrostatic potentials for the free and bound species and apparent pKa values for each ionizable residue, we show that C3d-CR2(SCR1–2) recognition is electrostatic in nature and involves not only the association interface, but also the whole molecules. Our results are in qualitative agreement with experimental data that measured the ionic strength and pH dependence of C3d-CR2 association. Also, our results for the native molecules and a number of theoretical mutants of C3d explain experimental mutagenesis studies of amino acid replacements away from the association interface that modulate binding of iC3b with full-length CR2. Finally, we discuss the packing of the two SCR domains. Overall, our data provide global and site-specific explanations of the physical causes that underlie the ionic strength dependence of C3d-CR2 association in a unified model that accounts for all experimental data, some of which were previously thought to be contradictory.

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Section: Length Of Cr2mentioning

confidence: 75%

The Electrostatic Nature of C3d-Complement Receptor 2 Association

Morikis

Lambris

2004

The Journal of Immunology

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“…This provides a link between the innate and the adaptive immune system (Carroll, 2004). Multiple studies have been performed on the interaction of CR2 with iC3b and C3dg (Clemenza and Isenman, 2000;Diefenbach and Isenman, 1995;Esparza et al, 1991;Kalli et al, 1991;Lambris et al, 1985;Lowell et al, 1989;Molina et al, 1995;Morikis and Lambris, 2004;Sarrias et al, 2001) (Fig. 2).…”

Section: C3b Fragments Signalingmentioning

confidence: 99%

Structural insights into the central complement component C3

Janssen

Gros

2007

Molecular Immunology

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C3 is a central protein of the complement system, which is important to immune defense and provides a link between innate and adaptive immunity. Three pathways of complement activation converge at the activation of C3 yielding a diverse set of biological responses. This versatile and flexible molecule interacts with various proteins to fulfill its functions. Here we review recent insights gained from the crystal structure determinations of human, native C3 and its physiological down-regulation product C3c. The data provided, for the first time, a complete and detailed view of the composition and arrangement of the domains in C3. Comparison of C3 with C3c indicates marked flexibility of the molecule, particularly in the ␣-chain. We discuss the observed domain rearrangements, conformational changes and the location of various protein binding sites. These detailed, and structural, insights are important for developing models of the molecular mechanisms underlying the diverse biological activities of this large and complex molecule.

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“…A region of amino acid sequence similarity in C3d and gp350/220 may well mediate the binding of these diverse proteins to CR2 (6,7,39). It will be of interest to determine whether CR2 interacts with C3d and gp350/220 via a specific sequence of amino acids and, if so, whether this sequence is found in a single repeating element.…”

Section: T W E P S a P V C E K E C Caatgcccaacccacatcgcacccatctccacmentioning

confidence: 99%

Molecular cloning of the cDNA encoding the Epstein-Barr virus/C3d receptor (complement receptor type 2) of human B lymphocytes.

Moore

Cooper²,

Tack³

et al. 1987

Proc. Natl. Acad. Sci. U.S.A.

145

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Complementary DNA clones for complement receptor type 2 (CR2), the B-lymphocyte membrane protein that serves as the receptor for Epstein-Barr virus and the C3d complement fragment, were obtained by screening a Xgtll library generated from Raji B lymphoblastoid cell mRNA. A 4.2-kilobase (kb) clone, representing the entire coding sequence of the protein plus untranslated 5' and 3' nucleotide sequences was obtained and sequenced. The 4.2-kb clone, which contains all but about 500 base pairs (bp) of the 5' untranslated region of the fufl-length CR2 mRNA, consists of 63 bp of 5' untranslated nucleotide sequence followed successively by a start codon, a 20-amino acid hydrophobic signal peptide, 1005 amino acids having a repeating motif, a 28-amino acid probable transmembrane domain, and a 34-amino acid cytoplasmic tail. The deduced amino acid sequence of the protein indicates that the extracellular domain consists entirely of 16 tandemly arranged repeating elements, each 60-75 amino acids in length, which are identified by multiple conserved residues. This repeating motif also occurs in the C3b/C4b receptor, several complement proteins, and a number of noncomplement proteins. In CR2, the 16 repeats occur in four clusters of four repeats each. Approximately 10% of the deduced amino acid sequence, including the amino and carboxyl termini, was conflirmed by amino acid sequencing of tryptic peptides derived from purified CR2. The nucleotide and derived amino acid sequence of CR2 and related studies are presented here.A Mr 145,000 B-lymphocyte membrane glycoprotein, designated complement receptor type 2 (CR2), serves as the receptor for Epstein-Barr virus (EBV) and the C3d and C3dg fragments of the third component of complement (1-5). An EBV viral envelope protein termed gp350/220 mediates the binding of EBV to CR2 (6, 7). Gp350/220 and C3d, the natural ligands, exhibit two regions of primary sequence similarity, a finding that suggests that common domains in these two proteins mediates binding to CR2. In addition to its role in permitting EBV infection, CR2 has been implicated in triggering B-cell activation (7-11); consistent with this finding, CR2 has been found to be phosphorylated upon treatment of B cells with phorbol myristate or anti-Ig (12).Previous studies have shown that the mature Mr 145,000 CR2 molecule consists of a Mr 111,000 polypeptide chain and multiple N-linked oligosaccharides (13). A previous study (14) reported the isolation of a partial CR2 cDNA clone and indicated that CR2 is highly similar to CR1, the C3b/C4b receptor; however, relatively limited nucleotide and protein sequence information was presented in that publication. The genes encoding both CR1 and CR2 have been mapped to human chromosome 1, band q32 (15).To further define the structural and functional properties of CR2, cDNA clones encoding CR2 were isolated, and the complete amino acid sequence of the protein* was deduced. Sequence analysis of tryptic peptides derived from purified CR2 allowed verification of the amino and carboxyl...

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Mapping of the C3d receptor (CR2)-binding site and a neoantigenic site in the C3d domain of the third component of complement.

Cited by 87 publications

References 36 publications

The Electrostatic Nature of C3d-Complement Receptor 2 Association

The Electrostatic Nature of C3d-Complement Receptor 2 Association

Structural insights into the central complement component C3

Molecular cloning of the cDNA encoding the Epstein-Barr virus/C3d receptor (complement receptor type 2) of human B lymphocytes.

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