The alternative pathway of complement

Pangburn, Michael K.; Müller‐Eberhard, Hans J.

doi:10.1007/bf01893019

Cited by 254 publications

(129 citation statements)

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“…Similarly, factor H prevents binding of factor B to C3b and dissociates Bb from the C3bBb complex (8). In addition, C4bp and factor H function as cofactors for the plasma protease factor I that mediates the degradation of C4b and C3b (5,6,9).…”

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confidence: 99%

The Complement Cofactor Protein (SBP1) from the Barred Sand Bass (Paralabrax nebulifer) Mediates Overlapping Regulatory Activities of Both Human C4b Binding Protein and Factor H

Kemper¹,

Zipfel²,

Gigli³

1998

Journal of Biological Chemistry

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We have previously shown that serum of the teleost fish barred sand bass (Paralabrax nebulifer) cleaves the ␣-chain of human C4b and C3b. The proteins that participate in these reactions were purified, and a specific protease and a single cofactor protein were identified. Functional characterization of the recombinantly expressed sand bass cofactor protein (SBP1) and truncated forms containing short consensus repeats (SCRs) 1-2, 1-3, 1-4, 1-5, and 12-17 revealed that SBP1 and SCRs 1-4 mediate the functional activities of the human plasma regulatory protein C4bp and factor H. They form a complex with C4b, inhibit the formation, and accelerate the decay of the classical pathway C3 convertase and display cofactor activity for the cleavage of C4b. In contrast, the interaction of SBP1 and SCRs 1-4 with human C3b in all these activities was limited. This difference is due to species-specific incompatibilities between the cofactor protein and human C3b. SBP1 and SCRs 1-5 displayed full binding and cofactor activity for methylamine-treated C3 from trout, a species closely related to the sand bass. The presence of only one cofactor in the fish plasma that combines the functional activities of C4bp and factor H demonstrates that the sand bass cofactor protein is the ancestral precursor to the two complement regulatory proteins in human plasma.In vertebrates, cleavage of the third component of complement (C3) 1 and subsequent assembly of the membrane attack complex (C5-C9) occur as functions of at least two distinct enzymes generated during the activation of the classical (1) and alternative (2, 3) pathways. The classical pathway C3 convertase is formed by a reaction involving the reversible binding of C2 to C4b in the presence of Mg 2ϩ to form the C4b2 complex and by the cleavage of the bound C2 by C1s to generate C4b2a (4). These reactions are remarkably similar to those occurring during the formation of the alternative pathway C3 convertase (2, 3). C3b binds to factor B, which is then cleaved by factor D to generate C3bBb. The formation and function of these two enzymes are regulated by three distinct mechanisms as follows: a temperature-dependent intrinsic decay of the enzymes; an extrinsic decay mediated by the effect of the serum proteins C4-binding protein (C4bp) and factor H, and the proteolytic inactivation of the ␣Ј-chain of C4b and C3b by factor I.

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confidence: 99%

The Complement Cofactor Protein (SBP1) from the Barred Sand Bass (Paralabrax nebulifer) Mediates Overlapping Regulatory Activities of Both Human C4b Binding Protein and Factor H

Kemper¹,

Zipfel²,

Gigli³

1998

Journal of Biological Chemistry

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“…The Xenopus C3 gene is shown not to be linked to the Xenopus major histocompatibility complex, as is also the case in mammals. Since the gene of the related molecule C4 is MHC-linked in both mammals and Xenopus, the C3 and C4 genes may have separated before Xenopus and mammals speciated.The third component of complement (C3) plays a central role in both the classical and alternative pathways of complement activation by interacting with numerous serum and surface complement proteins (1,2). In addition to being important for complement activation, C3 has been found to play a significant role in inflammatory processes and in the immune response (1, 3).…”

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confidence: 99%

Conservation of structural and functional domains in complement component C3 of Xenopus and mammals.

Grossberger¹,

Marcuz²,

Pasquier³

et al. 1989

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

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The cDNA sequence and the deduced amino acid sequence of the Mr 34,000 C-terminal fragment ofXenopus laevis complement component C3 are presented. The sequence of Xenopus C3 has 57% nucleotide identity to the corresponding sequence of human C3 and =49% amino acid identity to C3 from human, mouse, and rabbit. The Xenopus C3 sequence shows clusters of high and of low similarity to the mammalian C3 sequences. One of these regions of high similarity represents the domain of mammalian C3b involved in the binding of properdin, a regulator of the alternative pathway of complement activation. It is not clear whether the other highly conserved regions are involved in binding to other C3 ligands. The Xenopus C3 sequence completely lacks the Arg-Gly-Asp sequence, which has been suggested to be the recognition site of the human complement receptor type 3 on the iC3b fragment of human C3. The Xenopus C3 gene is shown not to be linked to the Xenopus major histocompatibility complex, as is also the case in mammals. Since the gene of the related molecule C4 is MHC-linked in both mammals and Xenopus, the C3 and C4 genes may have separated before Xenopus and mammals speciated.The third component of complement (C3) plays a central role in both the classical and alternative pathways of complement activation by interacting with numerous serum and surface complement proteins (1,2). In addition to being important for complement activation, C3 has been found to play a significant role in inflammatory processes and in the immune response (1, 3).Xenopus has both classical (4) and alternative (5, 6) pathways of complement activation. The complement proteins C3 (7) and C4 (4) isolated from Xenopus serum have subunit structures similar to mammalian C3 and C4. Human C3 fragment C3b is cleaved by Xenopus serum in a way similar to its cleavage by human serum, suggesting the presence of the regulatory proteins factors I and H in Xenopus serum (8). Receptors for Xenopus C3 fragments have been found on the surface ofXenopus macrophages (9), although it is not clear whether these are the Xenopus homologs of mammalian macrophage complement receptor type 1 (CR1) or 3 (CR3). Since the Xenopus C3 molecule shares many features with mammalian C3, including binding to mammalian CR1, properdin, and CS (10), comparison of the Xenopus C3 sequence with mammalian C3 sequences may reveal regions that are involved in binding to its many ligands as well as the structural elements of these interactions. Such regions are expected to be relatively conserved, since their rate of evolutionary divergence would be constrained by the rate of evolution of their ligands. (13).Preparation of Anti-Xenopus C3 Antibody. A rabbit antiXenopus C3 antiserum was prepared by using zymosanC3b/iC3b particles as described (7). The anti-Xenopus C3 antibody was afflinity-purified on zymosan coated with achain fragments of Xenopus C3. The coated zymosan was prepared by incubation in Xenopus serum and washing with 0.1% sodium dodecyl sulfate (SDS) containing 2% 2-mercaptoethanol....

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“…This latter reaction can be simulated by methylamine, which cleaves the thiol ester bond and forms the corresponding y-glutamylmethylamide [5]. As a result, the C3 and C4 proteins are supposed to undergo a conformational change as indicated by functional studies [6], spectroscopic studies [7, 81 and low-angle X-ray and neutron-scattering studies [9, 103; however, the detailed mechanism for this conformational change is not known. In order to make it possible to analyse the methylamine-induced conformational change of C3 in some detail, using small-angle scattering methods, we used monoclonal antibodies as markers.…”

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Large intramolecular movement in human complement protein C3 induced by methylamine

Österberg

Nilsson

Stigbrand

et al. 1989

European Journal of Biochemistry

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The reaction of methylamine with complement protein C3, which involves cleavage of a labile thiol ester bond, yields a large intramolecular rearrangement. This is shown by small-angle neutron and X-ray scattering using a Fab antibody as a marker. For the C3(Fab) 1 : 1 complex, the methylamine reaction yields an increase in the radius of gyration, R , from 4.6 nm to 6.0 nm. In the absence of Fab the corresponding R values increase from 4.4 nm to 5.1 nm. It is estimated that the methylamine-induced increase in R may correspond to a movement of the epitope to a position 5 nm away from the centre of gravity of the C3 molecule. In agreement with this finding, the maximum distance within the C3(Fab) complex increases from 16 nm to 22 nm as a result of the methylamine reaction. In order to explain this conformational change, it is tentatively suggested that the methylamine-induced cleavage of the C3 thiol ester bond leads to a domain rotation within the C3 molecule. In agreement with this idea, the data is consistent with a model which enables a globular domain within the molecule to rotate without redistributing the molecular mass more than that corresponding to the radii of gyration observed.The activation of the complement proteins C3 and C4 involves the cleavage of an N-terminal peptide from their a chains forming the fragments C3b and C4b, respectively. Simultaneously, a labile thiol ester bond is split, releasing a reactive glutamyl carboxylate group, which is capable of forming covalent bonds with either hydroxyl or amino groups [l -41. This latter reaction can be simulated by methylamine, which cleaves the thiol ester bond and forms the corresponding y-glutamylmethylamide [5]. As a result, the C3 and C4 proteins are supposed to undergo a conformational change as indicated by functional studies [6], spectroscopic studies [7, 81 and low-angle X-ray and neutron-scattering studies [9, 103; however, the detailed mechanism for this conformational change is not known. In order to make it possible to analyse the methylamine-induced conformational change of C3 in some detail, using small-angle scattering methods, we used monoclonal antibodies as markers. The Fab fragment rather than the IgG molecule was chosen due to its smaller size and the fact that the Fab fragment only has one reactive surface. The results indicate that a relatively dramatic increase in the radius of gyration occurs when the C3(Fab) 1:l complex reacts with methylamine. When going from the C3(Fab) complex to its methylamine derivative the increase in the radius of gyration is 30%.Correspondence to R. Osterberg, Department of Chemistry and Molecular Biology, Swedish University of Agricultural Sciences, Box 7015, S-75007 Uppsala, SwedenAbbreviations. SAXS, small-angle X-ray Scattering; SANS, smallangle neutron scattering. MATERIALS AND METHODS Prepurution of the samplesHuman C3 was prepared from fresh plasma as described previously [ll]. The C3 used contained approximately 2% free SH groups as determined by the incorporation of ['"CIiodoacetamide and w...

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The alternative pathway of complement

Cited by 254 publications

References 142 publications

The Complement Cofactor Protein (SBP1) from the Barred Sand Bass (Paralabrax nebulifer) Mediates Overlapping Regulatory Activities of Both Human C4b Binding Protein and Factor H

The Complement Cofactor Protein (SBP1) from the Barred Sand Bass (Paralabrax nebulifer) Mediates Overlapping Regulatory Activities of Both Human C4b Binding Protein and Factor H

Conservation of structural and functional domains in complement component C3 of Xenopus and mammals.

Large intramolecular movement in human complement protein C3 induced by methylamine

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