Substitution of a single amino acid (aspartic acid for histidine) converts the functional activity of human complement C4B to C4A.

The covalent binding of complement components C3 and C4 is critical for their activities. This reaction is made possible by the presence of an internal thioester in the native protein. Upon activation, which involves a conformational change initiated by the cleavage of a single peptide bond, the thioester becomes available to react with molecules with nucleophilic groups. This description is probably sufficient to account for the binding of the C4A isotype of human C4 to amino nucleophiles. The binding of the C4B isotype, and most likely C3, to hydroxyl nucleophiles, however, involves a histidine residue, which attacks the thioester to form an intramolecular acyl-imidazole bond. The released thiolate anion then acts as a base to catalyze the binding of hydroxyl nucleophiles, including water, to the acyl function. This mechanism allows the complement proteins to bind to the hydroxyl groups of carbohydrates found on all biological surfaces, including the components of bacterial cell walls. In addition, the fast hydrolysis of the thioester provides a means to contain this very damaging reaction to the immediate proximity of the site of activation.

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“…Ester bonds are sensitive to hydroxylamine treatment whereas amide bonds are resistant (Carroll et al, 1990). dS.K.A.…”

Section: The Autolytic Cleavage Reactionmentioning

confidence: 99%

The internal thioester and the covalent binding properties of the complement proteins C3 and C4

1997

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“…A His residue in the ␣ chain at position 1106 imparts to C4B the ability to form ester linkages. The presence of an Asp residue at position 1106 results in C4A functionality and preferential amide bond formation with target ONH 2 groups (56). Differences in the binding properties of C4A (amide) and C4B (ester) may have important functional consequences.…”

Section: Activation Of the Complement Systemmentioning

confidence: 99%

Infections of People with Complement Deficiencies and Patients Who Have Undergone Splenectomy

2010

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SUMMARY The complement system comprises several fluid-phase and membrane-associated proteins. Under physiological conditions, activation of the fluid-phase components of complement is maintained under tight control and complement activation occurs primarily on surfaces recognized as “nonself” in an attempt to minimize damage to bystander host cells. Membrane complement components act to limit complement activation on host cells or to facilitate uptake of antigens or microbes “tagged” with complement fragments. While this review focuses on the role of complement in infectious diseases, work over the past couple of decades has defined several important functions of complement distinct from that of combating infections. Activation of complement in the fluid phase can occur through the classical, lectin, or alternative pathway. Deficiencies of components of the classical pathway lead to the development of autoimmune disorders and predispose individuals to recurrent respiratory infections and infections caused by encapsulated organisms, including Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae. While no individual with complete mannan-binding lectin (MBL) deficiency has been identified, low MBL levels have been linked to predisposition to, or severity of, several diseases. It appears that MBL may play an important role in children, who have a relatively immature adaptive immune response. C3 is the point at which all complement pathways converge, and complete deficiency of C3 invariably leads to severe infections, including those caused by meningococci and pneumococci. Deficiencies of the alternative and terminal complement pathways result in an almost exclusive predisposition to invasive meningococcal disease. The spleen plays an important role in antigen processing and the production of antibodies. Splenic macrophages are critical in clearing opsonized encapsulated bacteria (such as pneumococci, meningococci, and Escherichia coli) and intraerythrocytic parasites such as those causing malaria and babesiosis, which explains the fulminant nature of these infections in persons with anatomic or functional asplenia. Paramount to the management of patients with complement deficiencies and asplenia is educating patients about their predisposition to infection and the importance of preventive immunizations and seeking prompt medical attention.

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“…Using site-directed mutagenesis at the cDNA level followed by expression of the modified proteins, it was found that the key residue lies in position 1106. The His at this position is crucial in conferring C4B-like binding acitivity whereas an Asp, Asn or Ala at this position renders the protein C4A-like [9,10]. Based on these observations, it was argued that the His of C4B plays a role in catalyzing the reaction of the thioester with hydroxyl groups on water and other compounds; thus, its reaction with amino groups is apparently less effective.…”

Section: Introductionmentioning

confidence: 99%

The effect of residue 1106 on the thioester‐mediated covalent binding reaction of human complement protein C4 and the monomeric rat α‐macroglobulin α₁I3

Ren¹,

Dodds²,

Enghild³

et al. 1995

FEBS Letters

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The histidine at position 1106 of the C4B isotype of human complement is involved in catalyzing the covalent binding of the thioester to glycerol and water. By replacing the histidine with other residues, it was found that tyrosine is also capable of mediating the reaction. We propose that they act as nucleophiles by first attacking the thioester, upon activation, to form acyl intermediates, which subsequently react with the hydroxyl groups of glycerol or water. The monomeric a-macroglobulin, ~113 of the rat, was also studied. Unlike ot2-macroglobulin , which is a tetramer, alI3 has binding properties similar to those of C4A.

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Substitution of a single amino acid (aspartic acid for histidine) converts the functional activity of human complement C4B to C4A.

Abstract: The

Cited by 102 publications

References 35 publications

The internal thioester and the covalent binding properties of the complement proteins C3 and C4

The internal thioester and the covalent binding properties of the complement proteins C3 and C4

Infections of People with Complement Deficiencies and Patients Who Have Undergone Splenectomy

The effect of residue 1106 on the thioester‐mediated covalent binding reaction of human complement protein C4 and the monomeric rat α‐macroglobulin α₁I3

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Substitution of a single amino acid (aspartic acid for histidine) converts the functional activity of human complement C4B to C4A.

Abstract: The

Cited by 102 publications

References 35 publications

The internal thioester and the covalent binding properties of the complement proteins C3 and C4

The internal thioester and the covalent binding properties of the complement proteins C3 and C4

Infections of People with Complement Deficiencies and Patients Who Have Undergone Splenectomy

The effect of residue 1106 on the thioester‐mediated covalent binding reaction of human complement protein C4 and the monomeric rat α‐macroglobulin α1I3

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The effect of residue 1106 on the thioester‐mediated covalent binding reaction of human complement protein C4 and the monomeric rat α‐macroglobulin α₁I3