The active site of human C4a anaphylatoxin

Hugli, Tony E.; Kawahara, Marleen; Unson, Cecilia G.; Molinar-Rode, R; Erickson, Bruce W.

doi:10.1016/0161-5890(83)90008-1

Cited by 21 publications

(8 citation statements)

References 13 publications

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“…Variations between the C-terminal pentapeptide AGLQR in C4a and the corresponding peptide LGLAR in C3a are particularly interesting changes because they result in functional consequences. Substitution of a glutamine in human C4a corresponding to the alanine at position 76 of C3a is largely responsible for the lower bioactivity of C4a relative to C3a as deduced from synthetic peptide studies [50].…”

Section: A Primary Structure Of C3a C4a and C5amentioning

confidence: 99%

“…A series of synthetic C4a peptides were prepared and characterized in the same manner as those of the C3a series [50]. Although these synthetic model peptides are considerably less active than the corresponding C3a peptides, the C-terminal pentaand octapeptides of C4a did exhibit measurable activity indicating that the "active The upper view projects a predominantly hydrophobic surface while the lower view shows the arginine cluster and a predominantly hydrophilic surface.…”

Section: C3a Analoguesmentioning

confidence: 99%

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Structure and function of the anaphylatoxins

Hugli

1984

Springer Semin Immunopathol

232

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Chemical and physical characterization of the anaphylatoxin molecules have provided a reasonably clear description of the architecture of these bioactive proteins. The primary structures of C3a, C4a, and C5a from man and from a number of animal species have been elucidated, and it is apparent that the three anaphylatoxins are genetically related. The anaphylatoxin protein chains very in length from 74 to 78 residues and no fewer than 30% of the residues are homologous when comparing C3a, C4a, and C5a within or between species. Synthetic peptide studies have been instrumental in identifying molecular features essential for the function of anaphylatoxins. Information gleaned from the structure-function studies with synthetic analogue peptides of the anaphylatoxins define putative "active sites" in these effector molecules. Linear sequences at the carboxy-terminus of C3a and C4a fulfill all of the criteria of an "active site," in that synthetic peptides of an identical sequence can mimic the biologic actions of the natural factors. In the case of human C3a, a crystallographic analysis has been performed and a three-dimensional structure was elucidated at the 3.2 A level. The crystalline structure of C3a provides valuable new information regarding the alpha helical regions and identifies the arrangement of intra-chain disulfide linkages. Taken together, the structural data now accumulated for anaphylatoxins permit molecular modelling of these proteins, designates favored conformational arrangements of the native structures, and specifically localizes the effector sites. Furthermore, elements at the essential active site have been defined with such precision that models are proposed detailing the exact nature of ligand interactions between anaphylatoxins and specific cellular receptors. Biologic characterization of the anaphylatoxins continues at a rapid pace and each advance provides a clearer view of the role of these humoral mediators in host defense. A variety of responses to anaphylatoxins are known to occur at the cellular level and are mediated in a hormone-like fashion. Diversity of action for these factors at the tissue level is readily explained by the numerous cell types stimulated by the anaphylatoxins. Cellular responses to the anaphylatoxins are perhaps the most easily defined and studied; however, tissue and systemic effects more accurately reflect the physiologic role of anaphylatoxins. Considerable progress has been made in understanding the mechanisms whereby anaphylatoxins mediate two major tissue effects, namely enhancement of vascular permeability and induction of smooth muscle contraction.(ABSTRACT TRUNCATED AT 400 WORDS)

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Section: A Primary Structure Of C3a C4a and C5amentioning

confidence: 99%

Section: C3a Analoguesmentioning

confidence: 99%

Structure and function of the anaphylatoxins

Hugli

1984

Springer Semin Immunopathol

232

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“…Functional- [5] and immunoblot assays [6,7] of plasma from HAE patients show degradation of high molecular weight kininogen (HK) into smaller fragments, compatible with liberation of bradykinin, the major mediator of edema formation. A kinin-like peptide cleaved off from C2b by plasmin [8], and C4a [9] are probably less important mediators. Fibrinolysis may be enhanced as shown by elevated plasmin-alpha-2-antiplasmin (PAP) complexes [10,11].…”

Section: Introductionmentioning

confidence: 99%

Activation of the Complement, Coagulation, Fibrinolytic and Kallikrein–Kinin Systems During Attacks of Hereditary Angioedema

Høgåsen

et al. 1996

Scand J Immunol

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Five patients with hereditary angioedema (HAE) were studied during attacks and remission as were healthy controls. The high levels of C1/C1-INH complexes, low C4 and high ratio C4 activation products (C4bc)/C4 also differed significantly during remission compared to controls. During attacks C4bc/C4 increased (922-2007; P = 0.022, remission versus attacks, median values throughout), C2 and CH50 dropped (111-31%; P = 0.043 and 110-36%; P = 0.016, respectively), TCC (C5b-9) increased (0.88-1.23 AU/ml; P = 0.028). Cleavage of HK increased to be almost complete during attacks (20-90%; P = 0.009). While factor XIa/serpin-complexes did not increase, a more than twofold rise in thrombin/antithrombin-complexes (0.20-0.50 microgram/l; P = 0.009) and in plasmin/alpha-2-antiplasmin-complexes (7.3-17 nmol/l; P = 0.028) was observed. For the first time cascade activation in HAE was studied simultaneously, and corroborates that attacks lead to activation of the kallikrein-kinin system, fibrinolysis and early part of the classical complement pathway. In addition, the authors present novel data of terminal complement and coagulation activation, the latter apparently not via FXIa.

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“…Amino acid substitutions were made systematically at positions 73-76 in order to elucidate the functionally important features of their side chains. Analogues 5, 7,18, 20, and 21 have been described previously (Caporale et al, 1980;Hugli et al, 1983).…”

Section: Resultsmentioning

confidence: 99%

“…Human C4a binds to the same cellular receptor as C3a but exhibits only 1% of the spasmogenic activity of C3a (Gorski et al, 1979). This low level of activity is due to replacement of Leu-73 by alanine and Ala-76 by glutamine (Hugli et al, 1983). We expect that bovine C4a should be significantly more active than human C4a because its active-site pentapeptide is the Val-73 analogue (5), which is essentially as active as C3a active-site peptide 1 in the ileal contraction assay.…”

Section: Discussionmentioning

confidence: 94%

Active site of C3a anaphylatoxin: contributions of the lipophilic and orienting residues

Unson¹,

Erickson²,

Hugli³

1984

Biochemistry

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Activation of the serum complement cascade generates C3a anaphylatoxin, a primary mediator of inflammation. The active-site pentapeptide from the COOH terminus of C3a, Leu-Gly-Leu-Ala-Arg (residues 73-77), exhibits the inflammatory activities and specificity of the native 77-residue polypeptide. Functionally important features of this active site were studied by testing the ability of 22 synthetic analogues of this pentapeptide to contract isolated muscle strips from guinea pig ileum and to desensitize this tissue to contraction induced by human C3a or C5a. The C3a receptors on mast cells and basophils probably contain lipophilic groups that interact with the lipophilic side chains of Leu-73 and Leu-75 and charged groups that interact with the carboxylate and guanidinium groups of Arg-77. The lipophilic contribution of Leu-73 is modest and sterically nonspecific while that of Leu-75 is substantial and sterically specific. Gly-74 and Ala-76 appear to position and orient the adjacent residues Leu-73, Leu-75, and Arg-77 for optimal receptor binding. The contribution of Gly-74 is neither conformationally nor sterically specific while that of Ala-76 is both conformationally and sterically specific. The cellular C3a receptors evidently interact most efficiently with peptides ending in -Leu-Ala-Arg-OH.

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The active site of human C4a anaphylatoxin

Cited by 21 publications

References 13 publications

Structure and function of the anaphylatoxins

Structure and function of the anaphylatoxins

Activation of the Complement, Coagulation, Fibrinolytic and Kallikrein–Kinin Systems During Attacks of Hereditary Angioedema

Active site of C3a anaphylatoxin: contributions of the lipophilic and orienting residues

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