Studies on C3 convertases. Inhibition of C5 convertase formation by peptides containing aromatic amino acids

Kossorotow, A; Opitz, W; Etschenberg, E.; Hadding, U.

doi:10.1042/bj1670377

Cited by 2 publications

(1 citation statement)

References 9 publications

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“…Based on cytoprotection assay results, we pinpointed that the exposed Phe123 of SCR-2 and Phe148 of SCR-3 are important for DAF-mediated complement protection. Our findings supporting the role of Phe123 and Phe148 are further strengthened by two observations: (i) binding of MAb IH4 that recognizes DAF and blocks its complementprotective function is also abolished by mutation of Phe148, and (ii) phenylalanine-containing peptides (25) and rosmarinic acid (which contains two aromatic rings) (46) inhibit complement, possibly by binding to C3b. We therefore propose that phenylalanine-containing peptides and rosmarinic acid conduct their inhibitory actions by binding to C3b via their correctly positioned aromatic groups that mimic the two closely positioned phenylalanines, 123 and 148, of DAF.…”

Section: Discussionmentioning

confidence: 54%

Structure-Function Analysis of Decay-Accelerating Factor: Identification of Residues Important for Binding of theEscherichia coliDr Adhesin and Complement Regulation

Hasan

Pawelczyk

Urvil³

et al. 2002

Infect Immun

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Decay-accelerating factor (DAF), a complement regulatory protein, also serves as a receptor for Dr adhesinbearing Escherichia coli. The repeat three of DAF was shown to be important in Dr adhesin binding and complement regulation. However, Dr adhesins do not bind to red blood cells with the rare polymorphism of DAF, designated Dr(a ؊ ); these cells contain a point mutation (Ser165-Leu) in DAF repeat three. In addition, monoclonal antibody IH4 specific against repeat three was shown to block both Dr adhesin binding and complement regulatory functions of DAF. Therefore, to identify residues important in binding of Dr adhesin and IH4 and in regulating complement, we mutated 11 amino acids-predominantly those in close proximity to Ser165 to alanine-and expressed these mutations in Chinese hamster ovary cells. To map the mutations, we built a homology model of repeat three based on the poxvirus complement inhibitory protein, using the EXDIS, DIAMOD, and FANTOM programs. We show that perhaps Ser155, and not Ser165, is the key amino acid that interacts with the Dr adhesin and amino acids Gly159, Tyr160, and Leu162 and also aids in binding Dr adhesin. The IH4 binding epitope contains residues Phe148, Ser155, and L171. Residues Phe123 and Phe148 at the interface of repeat 2-3, and also Phe154 in the repeat three cavity, were important for complement regulation. Our results show that residues affecting the tested functions are located on the same loop (148 to 171), at the same surface of repeat three, and that the Dr adhesin-binding and complement regulatory epitopes of DAF appear to be distinct and are Ϸ20 Å apart.

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Section: Discussionmentioning

confidence: 54%

Structure-Function Analysis of Decay-Accelerating Factor: Identification of Residues Important for Binding of theEscherichia coliDr Adhesin and Complement Regulation

Hasan

Pawelczyk

Urvil³

et al. 2002

Infect Immun

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Artificial inhibition of the complement system

et al. 2007

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A great number of natural substances affect the complement system in addition to its natural regulators. Among the complement effectors, the most important are inhibitors of the activation cascade. The necessity of searching for preparations capable of a purposeful effect on complement by inhibition of single stages of the activation cascade and without influence on its other functions is connected with the current importance of use in medicine of novel therapeutic regulators of the complement system. Important directions are the search for complement inhibitors that (a) interfere with the rejection of transplants; (b) can replace C1 inhibitor in hereditary angioedema, and (c) have a high anti-inflammatory activity in the therapy of rheumatic diseases, diabetes, and other autoimmune disorders. It is expedient to use the available techniques for the directed detection of the action of medicinal substances on complement, which allow the determination of their action on the complement system at various stages of the cascade of its activation.

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Studies on C3 convertases. Inhibition of C5 convertase formation by peptides containing aromatic amino acids

Abstract: The influence of various peptides containing the aromatic amino acids phenylalanine and tyrosine on the formation of the enzyme EAC1423 of the complement system from component C3 and enzyme EAC142 was investigated.

Cited by 2 publications

References 9 publications

Structure-Function Analysis of Decay-Accelerating Factor: Identification of Residues Important for Binding of theEscherichia coliDr Adhesin and Complement Regulation

Structure-Function Analysis of Decay-Accelerating Factor: Identification of Residues Important for Binding of theEscherichia coliDr Adhesin and Complement Regulation

Artificial inhibition of the complement system

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