Identification of a major human serum DNA-binding protein as β1H of the alternative pathway of complement activation

Gardner, William D.; White, Philip J.; Hoch, Sallie O.

doi:10.1016/s0006-291x(80)80187-2

Cited by 27 publications

(14 citation statements)

References 7 publications

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“…Similarly, factor H, but not C3b, bound to cells bearing high densities of surface sialic acid (Table 1). Factor H has been shown to be one of the two major DNA-binding proteins in human plasma (45) and can be selectively depleted from serum with sulfated Sephadex (39).…”

Section: Resultsmentioning

confidence: 99%

Discrimination between activators and nonactivators of the alternative pathway of complement: regulation via a sialic acid/polyanion binding site on factor H.

Meri

Pangburn

1990

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

353

254

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The alternative complement pathway is capable of discriminating human cells and tissues from a wide variety of potential pathogens. It has been recently demonstrated that attachment of complement component C3b to activator-derived molecules (e.g., small polysaccharides) restricts inactivation of C3b by factors H and I in a manner similar to activator surfaces. It is now shown that restriction is reversed by certain soluble polyanions (e.g., sialoglycopeptides, heparin, or dextran sulfate) that mimic the effects of sialic acid and glycosaminoglycans on human cells and tissues. Fluid-phase polyanions enhanced binding of factor H to C3b attached to activating particles, indicating that the effect resulted from increased affinity between C3b and factor H. The enhancement was specific for activator-bound C3b since no enhancement was observed on nonactivating particles. While several polyanions could cause this effect, some polyanions could not, indicating specificity. The active polyanions also inhibited lysis of cells via the alternative pathway. The binding site for sialic acid appears to reside on factor H, since factor H bound to heparin-agarose and to sialic acid-bearing fetuinagarose, whereas C3b bound to neither under the same conditions. These observations suggest that occupation of a specific site on factor H by polyanions induces an increase in the C3b-H affinity, resulting in discrimination of host cells and tissues from alternative pathway-activating foreign cells.The alternative pathway of complement (AP) represents a natural defense system for recognition and destruction of foreign organisms in vertebrate species (1-4). It enhances phagocytosis and is cytolytic for many bacteria, parasites, and virus-infected cells and for some tumor cells. This relatively simple system is composed of only six plasma glycoproteins (C3 and factors B, D, H, I, and P) but recognizes a wide variety of foreign organisms without prior contact or memory. The molecular mechanism by which C3b and the regulatory system of complement discriminate (5) between human and foreign particles has yet to be fully described. As an approach to this problem, a fluid-phase model for the AP recognition event has been constructed (6, 7). This paper shows that the recognition process can be fully mimicked with soluble complexes.

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Section: Resultsmentioning

confidence: 99%

Discrimination between activators and nonactivators of the alternative pathway of complement: regulation via a sialic acid/polyanion binding site on factor H.

Meri

Pangburn

1990

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

353

254

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“…(26) of this data suggests that HDP/LDH binds ss DNA with an affinity that is between 106 and 107 M-1 in 0.05 M NaCl (27), which compares with a value of 1014 M-1 for E. coli SSB under the same conditions (unpublished data). In addition, several other proteins, including the P-1 protein (protocollagen precursor) from fibroblasts (28), a-1-antichymotrypsin (29), and three serum proteins involved in complement activation: C3DP (30), factor B (31), and f31H, (32) that apparently have no in vivo role in DNA metabolism nonetheless bind to ss DNA-cellulose. Taken together, these data indicate that some care needs to be exercised in ascribing in vivo functions simply on the basis of binding to ss DNA-cellulose (2) or acting as a helix-destabilizing protein in vitro.…”

Section: Discussionmentioning

confidence: 99%

Identification of a nucleic acid helix-destabilizing protein from rat liver as lactate dehydrogenase-5.

Williams¹,

Reddigari²,

Patel³

1985

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

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A rat liver DNA helix-destabilizing protein (HDP) that has previously been proposed to play a role in transcription has been identified as M chain lactate dehydrogenase (LDH-5; L-lactate:NAD+ oxidoreductase, EC 1.1.1.27). Tryptic peptides accounting for 157 amino acids in the rat liver HDP have been characterized and then matched to the published sequence for the M chain of porcine LDH. Based on amino acid compositions and direct solid-phase protein sequencing, at least 148 of the 157 residues that were compared are identical in both proteins. In addition, both porcine LDH and the rat liver HDP have blocked amino termini and similar amino acid compositions and molecular weights. Rat liver HDP and LDH-5 that were purified to molecular homogeneity had similar specific activities in both single-stranded DNA (ss DNA) binding and LDH assays. HPLC tryptic peptide maps were also identical for both the rat liver HDP and LDH proteins. Since preincubation of HDP in NADH prevents its binding to ss DNA, both NADH and ss DNA may be binding at the same site. Further support for this latter idea derives from chemicalmodification studies which demonstrate that tyrosine-238, which is located near the coenzyme binding site of LDH, seems to be essential for the ability of HDP to bind ss DNA. These results indicate caution in ascribing in vivo roles solely on the basis of binding to ss DNA. Alternatively, they suggest that a single protein may play more than one biological role.

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“…H was isolated from a pool of enriched fractions after DEAE Sephacel chromatography. Contaminants were removed by passage over DNA cellulose (Sigma Chemical Co.) in 10 mM sodium phosphate, pH 6.8, 50 mM sodium chloride, 5 mM EDTA, and elution by a gradient to 0.4 M sodium chloride (20). C3 and H were also isolated from a pool of sera drawn on several dates from a patient with SLE who consistently demonstrated excess inhibitor.…”

Section: Methodsmentioning

confidence: 99%

A circulating inhibitor of fluid-phase amplification. C3 convertase formation in systemic lupus erythematosus.

Waldo¹,

Forristal²,

Beischel³

et al. 1985

J. Clin. Invest.

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Identification of a major human serum DNA-binding protein as β1H of the alternative pathway of complement activation

Cited by 27 publications

References 7 publications

Discrimination between activators and nonactivators of the alternative pathway of complement: regulation via a sialic acid/polyanion binding site on factor H.

Discrimination between activators and nonactivators of the alternative pathway of complement: regulation via a sialic acid/polyanion binding site on factor H.

Identification of a nucleic acid helix-destabilizing protein from rat liver as lactate dehydrogenase-5.

A circulating inhibitor of fluid-phase amplification. C3 convertase formation in systemic lupus erythematosus.

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