Molecular modeling and mechanism of action of human decay-accelerating factor

Kuttner-Kondo, Lisa; Me, Medof; Brodbeck, William G.; Shoham, Menachem

doi:10.1093/protein/9.12.1143

Cited by 53 publications

(43 citation statements)

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“…This is significantly extended, by almost 50%, when compared with previous models (22,25). Alternative topologies are possible if the observed linearity of the SCR34 interface is not repeated at the junctions of the other SCR domains.…”

Section: Discussionmentioning

confidence: 74%

“…A recent low resolution structure of CD55 complexed with EV7 (26) is essentially linear along the SCR2-3 junction but exhibits a distinct angle at the interface between SCR1 and -2. Until a high resolution structure of a four SCR domain CD55 molecule is determined, it is important that the functional data concerning SCRs 1 and 2 are interpreted in the light of a variety of architectural models, of which our structure-based model and earlier homology models of Kuttner-Kondo et al (25) represent the extremes available.…”

Section: Discussionmentioning

confidence: 99%

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Mapping CD55 Function

Williams

Chaudhry

Goodfellow

et al. 2003

Journal of Biological Chemistry

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Decay-accelerating factor (CD55), a regulator of the alternative and classical pathways of complement activation, is expressed on all serum-exposed cells. It is used by pathogens, including many enteroviruses and uropathogenic Escherichia coli, as a receptor prior to infection. We describe the x-ray structure of a pathogen-binding fragment of human CD55 at 1.7 Å resolution containing two of the three domains required for regulation of human complement. We have used mutagenesis to map biological functions onto the molecule; decayaccelerating activity maps to a single face of the molecule, whereas bacterial and viral pathogens recognize a variety of different sites on CD55.

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Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Mapping CD55 Function

Williams

Chaudhry

Goodfellow

et al. 2003

Journal of Biological Chemistry

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“…SCR3 has been implicated in regulatory function in various studies including Abblocking and mutation studies. Molecular modeling has highlighted two regions that might interact with convertases, a stretch of positively charged amino acids (KKK 125-127 ) predicted to lie in the groove between SCRs 2 and 3, and a hydrophobic patch (L 147 F 148 ) located on the surface of SCR3 (28). Indeed, these amino acids are highly conserved across species.…”

Section: Discussionmentioning

confidence: 99%

Decay-Accelerating Factor Must Bind Both Components of the Complement Alternative Pathway C3 Convertase to Mediate Efficient Decay

Harris

Pettigrew

Lea

et al. 2007

The Journal of Immunology

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Decay-accelerating factor (DAF; CD55) inhibits the complement (C) cascade by dissociating the multimolecular C3 convertase enzymes central to amplification. We have previously demonstrated using surface plasmon resonance (Biacore International) that DAF mediates decay of the alternative pathway C3 convertase, C3bBb, but not of the inactive proenzyme, C3bB, and have shown that the major site of interaction is with the larger cleavage subunit factor B (Bb) subunit. In this study, we dissect these interactions and demonstrate that the second short consensus repeat (SCR) domain of DAF (SCR2) interacts only with Bb, whereas SCR4 interacts with C3b. Despite earlier studies that found SCR3 to be critical to DAF activity, we find that SCR3 does not directly interact with either subunit. Furthermore, we demonstrate that properdin, a positive regulator of the alternative pathway, does not directly interact with DAF. Extending from studies of binding to decay-accelerating activity, we show that truncated forms of DAF consisting of SCRs 2 and 3 bind the convertase stably via SCR2-Bb interactions but have little functional activity. In contrast, an SCR34 construct mediates decay acceleration, presumably due to SCR4-C3b interactions demonstrated above, because SCR3 alone has no binding or functional effect. We propose that DAF interacts with C3bBb through major sites in SCR2 and SCR4. Binding to Bb via SCR2 increases avidity of binding, concentrating DAF on the active convertase, whereas more transient interactions through SCR4 with C3b directly mediate decay acceleration. These data provide new insights into the mechanisms involved in C3 convertase decay by DAF.

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“…The molecular modeling of DAF CCP1-4 based on the NMR-determined solution structure of factor H CCP15-16 (4) was conducted in an earlier paper (3). The modeling involved the use of program O (26) for residue changes, residue insertions, and connection of CCPs, whereas the program LSQKAB within the CCP4 suite of crystallographic programs (27) was used for superpositioning of DAF CCPs onto the factor H structure.…”

Section: Modelingmentioning

confidence: 99%

“…Fig. 1A shows the positions of the mutated residues on the factor H-based DAF model (3). In CCP2, one of the eight mutations, R96A, abolished DAA (Ͻ1%) and two others, R69A and R100A, markedly reduced DAA (Յ12%) in the alternative pathway.…”

Section: Identification Of Daf Amino Acids Critical For Decay Accelermentioning

confidence: 99%

Characterization of the Active Sites in Decay-Accelerating Factor

Kuttner-Kondo

Mitchell

Hourcade

et al. 2001

The Journal of Immunology

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Decay-accelerating factor (DAF) is a complement regulator that dissociates autologous C3 convertases, which assemble on self cell surfaces. Its activity resides in the last three of its four complement control protein repeats (CCP2–4). Previous modeling on the nuclear magnetic resonance structure of CCP15–16 in the serum C3 convertase regulator factor H proposed a positively charged surface area on CCP2 extending into CCP3, and hydrophobic moieties between CCPs 2 and 3 as being primary convertase-interactive sites. To map the residues providing for the activity of DAF, we analyzed the functions of 31 primarily alanine substitution mutants based in part on this model. Replacing R69, R96, R100, and K127 in the positively charged CCP2–3 groove or hydrophobic F148 and L171 in CCP3 markedly impaired the function of DAF in both activation pathways. Significantly, mutations of K126 and F169 and of R206 and R212 in downstream CCP4 selectively reduced alternative pathway activity without affecting classical pathway activity. Rhesus macaque DAF has all the above human critical residues except for F169, which is an L, and its CCPs exhibited full activity against the human classical pathway C3 convertase. The recombinants whose function was preferentially impaired against the alternative pathway C3bBb compared with the classical pathway C4b2a were tested in classical pathway C5 convertase (C4b2a3b) assays. The effects on C4b2a and C4b2a3b were comparable, indicating that DAF functions similarly on the two enzymes. When CCP2–3 of DAF were oriented according to the crystal structure of CCP1–2 of membrane cofactor protein, the essential residues formed a contiguous region, suggesting a similar spatial relationship.

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Molecular modeling and mechanism of action of human decay-accelerating factor

Cited by 53 publications

References 0 publications

Mapping CD55 Function

Mapping CD55 Function

Decay-Accelerating Factor Must Bind Both Components of the Complement Alternative Pathway C3 Convertase to Mediate Efficient Decay

Characterization of the Active Sites in Decay-Accelerating Factor

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