C1- inhibitors and their genes: an update.
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Angioedema↗
Biomedical subjects
V H Donaldson
Publications and source records attributed to V H Donaldson.
Angioneurotic edema with acquired C1- inhibitor deficiency and autoantibody to C1- inhibitor: response to plasmapheresis and cytotoxic therapy.
A patient with severe acquired angioneurotic edema had essentially no C1- inhibitor activity in his serum and nearly died of cardiopulmonary arrest during an acute episode of facial, oral, and pharyngeal edema. This patient had an antibody directed against C1- inhibitor and C1- inhibitor-anti-C1- inhibitor complexes in his serum. The antibody required a normal residue (Arg) in the reactive center of the inhibitor for its optimal interaction with the inhibitor. Plasmapheresis with 5% human serum albumin replacement relieved him of his antibody load and the edema; additional treatment with pulsed cyclophosphamide has provided a sustained remission. The 5% albumin solution that was used contained functional C1- inhibitor; other lots that were tested contained only traces or none. No underlying disease has yet been identified. During this acute episode of edema, the C1- inhibitor in the patient's plasma was a 92 kd component, and on recovery, a 105 kd component reappeared. C1- inhibitor isolated from the patient's plasma, which was obtained before pheresis, was mainly in lower molecular weight forms (56 kd and 45 kd). The antibody in the patient's serum appeared to render C1- inhibitor susceptible to proteolysis, for when purified antibody was added to normal serum, a cleaved form of C1- inhibitor was generated.
Angioedema↗
Interactions of C1(-)-inhibitors from normal persons and patients with type II hereditary angioneurotic edema with purified activated Hageman factor (factor XIIa).
Activated high molecular weight Hageman factor (75 Kd) and Hageman factor carboxy-terminal fragments both formed complexes with purified C1(-)-inhibitor, but the Hageman factor fragments appeared to have a higher affinity for the C1(-)-inhibitor than activated Hageman factor. Therefore, the clot-promoting activity of activated Hageman factor might be relatively unimpaired if Hageman factor fragments are also present. Normal C1(-)-inhibitor was cleaved by Hageman factor fragments. Clot-promoting activity was not generated in Hageman factor by exposure to Hageman factor fragments, nor was Hageman factor cleaved by Hageman factor fragments. When Hageman factor was cleaved by streptokinase-activated plasminogen, a 40 Kd fragment was released. In contrast to their interactions with other proteinases, which are blocked by normal C1(-)-inhibitor, Type II C1(-)-inhibitors from plasmas of affected members of eight different kindred with this form of hereditary angioneurotic edema all inhibited the specific coagulant activity of activated Hageman factor to some degree. They did not all form complexes with activated Hageman factor that were stable during sodium dodecyl sulfate-polyacrylamide gel electrophoresis.
Angioedema↗
CpG mutations in the reactive site of human C1 inhibitor.
C1 inhibitor plays an important role in the regulation of vascular permeability through its ability to inactivate enzymes which release polypeptide kinins. Dysfunctional C1 inhibitor molecules are present in the plasma of affected members of the Da and Ri hereditary angioneurotic edema kindreds. We constructed genomic libraries from Da and Ri patient DNAs which had been cleaved with BclI to generate a fragment containing 21 kilobases of the C1 inhibitor locus. C1 inhibitor gene-containing recombinants originating from mutant Da and Ri alleles were differentiated from those derived from normal alleles by linkage analysis using the intragenic HgiAI restriction fragment length polymorphism. Nucleotide sequencing of the complete protein-coding regions of the mutant alleles identified two different mutations in a CpG dinucleotide corresponding to the first two bases of arginine codon 444. These single base mutations changed the identity of the functionally critical P1 reactive site residue from arginine to cysteine (Da) or histidine (Ri). The additional cysteine residue in C1 inhibitor Da suggests how it is covalently bound to albumin in plasma. The presence of CpG dinucleotides in the codons specifying the P1 arginines of C1 inhibitor and antithrombin III explains the high incidence of histidine and cysteine substitutions observed among dysfunctional mutants of these serine protease inhibitors.
Alleles↗
Danazol.
Danazol is a synthetic attenuated androgen that can interfere with normal interactions between the pituitary-hypothalamic axis and the gonads. These effects are mediated by complex mechanisms, including those in which danazol can compete with natural steroids in binding to androgen receptors or to sex hormone-binding globulin, possibly displacing natural steroids from this protein, and in binding to reactive sites of enzymes required for synthesis of natural steroids, thereby depressing synthesis. Because of danazol's impairment of the pituitary-hypothalamic interactions with gonads, it is an effective therapeutic agent for treatment of endometriosis and cystic disease of the breast. It is effective in the treatment of hereditary angioneurotic edema, but the mechanism of this therapeutic success is unclear. Danazol has been used, without universal success, in the treatment of other gynecologic and certain hematologic disorders.
Blood Proteins↗
C1-inhibitor in hereditary angioneurotic edema: types I and II.
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Angioedema↗
Angioedema induced by a peptide derived from complement component C2.
Synthetic peptides that correspond to the COOH-terminal portion of C2b enhance vascular permeability in human and guinea pig skin. In human studies, 1 nmol of the most active peptide of 25-amino acid residues produced substantial local edema. A pentapeptide and a heptapeptide corresponding to the COOH-terminal sequence of C2b each induced contraction of estrous rat uterus in the micromole range; a peptide of 25 amino acids from this region induced a like contraction of rat uterus at a concentration 20-fold lower than the smaller peptides. The vascular permeability of guinea pig skin was enhanced by doses of these synthetic peptides in a similar fashion as that observed for the concentration of rat uterus. The induction of localized edema by intradermal injection in both the guinea pig and the human proceeds in the presence of antihistaminic drugs, suggesting that there is a histamine-independent component to the observed increase in vascular permeability. Cleavage of C2 with the enzymic subcomponent of C1, C1s, yields only C2a and C2b, and no small peptides, whereas cleavage of C2 with C1s and plasmin yields a set of small peptides. These plasmin-cleaved peptides are derived from the COOH terminus of C2b, and they induce the contraction of estrous rat uterus.
Amino Acid Sequence↗
Comparison of properties of monoclonal and polyclonal antibodies against the light chain of human high molecular weight kininogen.
A murine hybridoma monoclonal line-secreted antibody (C3G5) against the light chain of human high molecular weight kininogen (HMWK), which consisted of gamma-1 kappa isotype, was largely composed of 190 kd molecules, and gave an optimal reaction when used in an equimolar concentration with HMWK. It did not influence the initial digestion of HMWK or the amount of kinin released by kallikrein. Pretreatment of HMWK with C3G5 antibodies did not augment or inhibit its coagulant properties, nor did pretreatment interfere with its adsorption on kaolin or on the ion-exchange resin diethylaminoethyl (DEAE) Sephadex A-50. The epitope that reacted with this antibody was localized to a portion of the light chain within 6 kd of the carboxy-terminus of the molecule near the single cysteine of this chain, at residue 614. This monoclonal antibody reacted with an epitope that was stable during early plasmin digestion. The amounts of antigens reactive with a polyclonal antibody to the light chain were increased during the same period of plasmin digestion. Prolonged plasmin digestion reduced the amounts of both types of light chain antigens. During kallikrein digestion, the amount of epitope reactive with C3G5 antibody was unaffected, whereas the concentration of antigens detected with polyclonal anti-light chain antibodies was increased throughout digestion. Therefore, light chain antigens reactive with the polyclonal antibody are probably in the interior of the uncleaved molecule and become exposed after initial cleavage, which probably facilitates changes in the conformation of the molecule. The epitope reactive with monoclonal antibodies is probably on the surface of the uncleaved molecule.
Animals↗
Comparison of human high molecular weight kininogen digestion by plasma kallikrein and by plasmin. A revised method of purification of high molecular weight kininogen.
Both kallikrein and plasmin readily released 112,000 and 102,000 molecular weight derivatives from purified human high molecular weight (HMW)-kininogen. In each instance, these early digestion products were composed of disulfide-linked chains of 64,000 and 58,000 molecular weights. Under the experimental conditions used, kallikrein failed to release additional cleavage fragments from HMW-kininogen when it had been previously digested by plasmin, whereas HMW-kininogen pretreated with kallikrein was then cleaved by plasmin into several derivatives of decreasing molecular size. The profound molecular changes induced by plasmin were only accompanied by partial kinin release. Plasmin cleavage dissociated procoagulant activity from at least one antigenic site of HMW-kininogen light chain. Moreover, kinin activity could be released from a cleavage product of HMW-kininogen containing light but not heavy chain antigens, indicating that plasmin had cleaved this kininogen on the N-terminal side of the bradykinin region of the molecule. Cleavage of HMW-kininogen by kallikrein readily released bradykinin, whereas kinin release by plasmin was slower and the cleavage pattern different. It is, therefore, unlikely that plasmin is a major source of bradykinin release in plasma. A method of isolating HMW-kininogen from human plasma is described that provides a homogeneous single band of kininogen, with a recovery of approximately 44% with respect to that in plasma in a period of 5 days.
Chromatography↗
Interactions of plasma kallikrein and C1-s with normal and dysfunctional C1(-)-inhibitor proteins from patients with hereditary angioneurotic edema: analytic gel studies.
Purified preparations of normal C1(-)-inhibitor (C1(-)-INH) formed high mol wt complexes with plasma kallikrein that were stable during sodium dodecyl sulfate (SDS)-gel electrophoresis, but most of the dysfunctional C1(-)-INH proteins isolated from plasma of patients with type II hereditary angioneurotic edema (HANE) did not. Two of eight dysfunctional C1(-)-INH proteins were cleaved to lower mol wt forms that were not seen following the reaction of normal C1(-)-INH with equimolar amounts, or less, of plasma kallikrein. Only the higher mol wt component of normal C1(-)-INH (106,000 mol wt) appeared to form a stable complex with the plasma kallikrein, whereas both the 106,000 and 96,000 mol wt forms made stable complexes with C1-s. When a preparation of normal C1(-)-INH containing a homogeneous single band of C1(-)-INH was exposed to C1-s or kallikrein, a "doublet" form evolved in which the heaviest band was in the original position of native C1(-)-INH; C1-s cleavage provided a second band of 96,000; and cleavage by kallikrein, a second band of 94,000 mol wt. We conclude that dysfunctional C1(-)-INH proteins from plasma of persons with type II hereditary angioneurotic edema have impaired interactions with plasma kallikrein and are heterogeneous with respect to these interactions. Moreover, the requirements for the formation of stable complexes between normal C1(-)-INH and plasma kallikrein differed from those for stable complex formation with C1-s. The doublet form of C1(-)-INH, which purified preparations frequently demonstrate, may be due to prior cleavage by C1-s or kallikrein.
Angioedema↗
Human C1 inhibitor: primary structure, cDNA cloning, and chromosomal localization.
The primary structure of human C1 inhibitor was determined by peptide and DNA sequencing. The single-chain polypeptide moiety of the intact inhibitor is 478 residues (52,869 Da), accounting for only 51% of the apparent molecular mass of the circulating protein (104,000 Da). The positions of six glucosamine-based and five galactosamine-based oligosaccharides were determined. Another nine threonine residues are probably also glycosylated. Most of the carbohydrate prosthetic groups (probably 17) are located at the amino-terminal end (residues 1-120) of the protein and are particularly concentrated in a region where the tetrapeptide sequence Glx-Pro-Thr-Thr, and variants thereof, is repeated 7 times. No phosphate was detected in C1 inhibitor. Two disulfide bridges connect cysteine-101 to cysteine-406 and cysteine-108 to cysteine-183. Comparison of the amino acid and cDNA sequences indicates that secretion is mediated by a 22-residue signal peptide and that further proteolytic processing does not occur. C1 inhibitor is a member of the large serine protease inhibitor (serpin) gene family. The homology concerns residues 120 through the C-terminus. The sequence was compared with those of nine other serpins, and conserved and nonconserved regions correlated with elements in the tertiary structure of alpha 1-antitrypsin. The C1 inhibitor gene maps to chromosome 11, p11.2-q13. C1 inhibitor genes of patients from four hereditary angioneurotic edema kindreds do not have obvious deletions or rearrangements in the C1 inhibitor locus. A HgiAI DNA polymorphism, identified following the observation of sequence variants, will be useful as a linkage marker in studies of mutant C1 inhibitor genes.
Amino Acid Sequence↗
Scission of human apolipoprotein B-100 by kallikrein: characterization of the cleavage site.
Low density lipoprotein (LDL) from human plasma was digested with the specific endoprotease, kallikrein. Apolipoprotein B-100, the protein moiety of LDL, was cleaved by kallikrein into two fragments (K1 and K2) which we have compared to the naturally occurring fragments, B-74 and B-26. We have found that K1 and K2 precisely match B-74 and B-26 with respect to molecular weight, stoichiometry, and amino terminal amino acid sequence. These findings provide strong evidence that kallikrein is the agent responsible for the formation of B-74 and B-26 in human LDL.
Amino Acid Sequence↗
Processing of apolipoprotein B-100 of human plasma low density lipoproteins by tissue and plasma kallikreins.
Human plasma low density lipoproteins (LDL) are the major carriers of cholesterol and cholesteryl esters in the circulation. Their increased levels correlate positively with increased risk of coronary artery disease. LDL contain a single major apolipoprotein of apparent molecular weight (Mr) = 550,000, designated apolipoprotein B-100 (apoB-100), and in some LDL preparations, minor components termed apoB-74 (410,000) and apoB-26 (145,000). The structural relationship of the apoB-74 and -26 proteins to the apoB-100 has remained obscure and their roles in cholesterol metabolism are unknown. In the present study, we show that the addition of kaolin to plasma anticoagulated with EDTA induces the proteolytic cleavage of apoB-100. As a result, two apoB peptides are produced with Mr indistinguishable from plasma apoB-74 and -26. The specific cleavage of apoB-100 was mimicked in vitro by purified human plasma and tissue kallikreins. In contrast, thrombin, factor Xa, plasmin, trypsin, and chymotrypsin did not produce these peptides when incubated with LDL. The findings of the study suggest that apoB-74 and -26 are proteolytic fragments of apoB-100 and that the endogenous protease has a kallikrein-like specificity for DLD-apoB-100. The role of plasma and tissue kallikreins in cholesterol metabolism remains to be determined.
Apolipoprotein B-100↗
Purification of Hageman factor (factor XII) on columns of popcorn-agarose.
Purification of Hageman factor (HF, factor XII) from human plasma is a tedious procedure and the product is not always in the precursor form. Hojima has described a protein derived from corn kernels that inhibits the enzymatic properties of HF. This inhibitor binds to the precursor form of HF. Rapid purification of HF was achieved by using as the major purification step adsorption of this clotting factor to popcorn inhibitor bound to agarose. The product had a specific activity of 50.0 to 67.1 coagulant units of HF per milligram protein, and the yield was 33% to 40% of the HF content of the starting plasma. The purified protein displayed a single band upon unreduced or reduced sodium dodecyl sulfate polyacrylamide gel electrophoresis and less than 0.1% was in an activated form, as measured in coagulant assays. The technique described is more rapid and reliable than methods described earlier.
Adsorption↗
Variability in purified dysfunctional C1(-)-inhibitor proteins from patients with hereditary angioneurotic edema. Functional and analytical gel studies.
C1(-)-inhibitor (C1(-)-INH) proteins from normal persons and members of eight different kindred with dysfunctional C1(-)-INH proteins associated with hereditary angioneurotic edema (HANE) were compared with respect to their inhibitory activity against purified preparations of C1s-, plasma kallikrein, activated forms of Hageman factor, and plasmin. Each dysfunctional C1(-)-INH protein showed a unique spectrum of inhibitory activity against these enzymes. Although none of the dysfunctional C1(-)-INH proteins significantly impaired amidolysis by plasmin, all but one inhibited activated Hageman factor. One purified dysfunctional C1(-)-INH (Ta) inhibited purified C1s- to a normal degree. Another C1(-)-INH (Za) had almost seven times as much inhibitory activity as normal C1(-)-INH against activated Hageman factor, but had decreased activity against C1s- and no activity against plasmin. Analyses of mixtures of plasmin and C1(-)-INH proteins in SDS gel electrophoresis revealed variability in the patterns of complex formation and cleavage of dysfunctional proteins after exposure to C1s- and plasmin. Some bound to plasmin and were cleaved, even though none significantly impaired the amidolytic activity of plasmin. Two were cleaved by C1s-, whereas neither normal or other dysfunctional C1(-)-INH were cleaved. Dysfunctional C1(-)-INH proteins from patients with HANE are thus heterogeneous in their inhibitory properties and there must be different structural requirements for the inhibition of the various plasma enzymes that can be regulated by normal C1(-)-INH. The data suggest that in addition to common sites of interactions between these proteases and C1(-)-INH, there are also points of contact that are specific for each protease. Genetic mutations leading to structural changes at some of these sites may have differing effects on the interaction between individual proteases and abnormal C1(-)-INH proteins. These alterations may allow these proteins to serve as probes for structural requirements for inhibitory actions of normal C1(-)-INH.
Angioedema↗
The role of plasmin in kinin-release by preparations of human thrombin.
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Animals↗
Hereditary angioneurotic edema.
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Adolescent↗
Phylogenetic heterogeneity of plasma kininogens.
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Animals↗