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815 records · Page 46Linked to original sources
PubMed1996

Characterization of C1 inhibitor-Ta. A dysfunctional C1INH with deletion of lysine 251.

Dysfunctional C1 inhibitor (C1INH)-Ta is a naturally occurring mutant from a patient with type II hereditary angioedema. This mutant has a deletion of the codon for Lys-251, which is located in the connecting strand between helix F and strand 3A, overlying beta sheet A. Deletion of this Lys modifies the amino acid sequence at this position from Asn-Lys-Ile-Ser to Asn-Ile-Ser and creates a new glycosylation site. To further characterize the mechanism of dysfunction, we have analyzed the recombinant normal and Ta proteins expressed by COS cells in addition to the proteins in serum and isolated from serum. Recombinant C1INH-Ta revealed an intermediate thermal stability in comparison with the intact and reactive center cleaved normal proteins. Analysis of the reactivity of this recombinant protein with target proteases demonstrated no complex formation with C1s, C1r, or kallikrein. Inefficient complex formation was, however, clearly detectable with beta-factor XIIa. Each protease produced partial cleavage of the recombinant mutant inhibitor. Recombinant C1INH-Ta, on 7.5% SDS-polyacrylamide gel electrophoresis and by size fractionation on Superose 12, showed a higher molecular weight fraction that was compatible in size with dimer formation. However, no multimerization of C1INH-Ta isolated from serum or of C1INH-Ta in serum, was observed. The C1INH-Ta dimer expressed the epitopes that normally are expressed only on the protease complexed or the cleaved inhibitor. These epitopes were not expressed on the monomeric inhibitor. The data suggest that the mutation in C1INH-Ta results in a folding abnormality that behaves as if it consists of two populations of molecules, one of which is susceptible to multimerization and one of which is converted to a substrate, but which retains residual inhibitory activity.

Animals↗
PubMed1990

Interaction of C1q with its receptor on cultured cell lines induces an anti-proliferative response.

The receptor for human C1q (C1qR) is expressed on a wide variety of somatic cells, including cultured cell lines of different lineages such as Raji, Daudi, Wil2WT, U937, and Molt4. In this report, we present evidence which shows that culturing of C1qR-expressing cell lines with C1q inhibits their growth. When each of the different cell lines were cultured for 5 days with or without various concentrations (5-50 micrograms/ml) of micro-filtered (0.22 micron) C1q, cell proliferation was inhibited in a dose-dependent manner with maximal inhibition (90%) occurring at a concentration of 50 micrograms/ml at Day 4 of culture. This anti-proliferative effect of C1q was inhibited when 30 micrograms/ml of F(ab')2 anti-C1q was included in the culture with C1q while the antibody alone did not have any effect. The specificity of this interaction was further substantiated by the finding that neither macromolecular C1, or subcomponents C1r and C1s, nor human or murine IgG nor IgM had any inhibitory activity when cultured with these cell lines. That this C1q-induced inhibition of cell growth is mediated by C1qR was deduced from experiments in which (i) culturing of cells in the presence of two IgM monoclonal antibodies II1/D1 and II1/B5, directed against the C1q-binding site of C1qR resulted in the inhibition of cell growth while nonimmune murine IgM did not, and (ii) the collagenous portion of C1q (c-C1q) which contains the intact, C1qR-binding domain was also capable of inhibiting cell proliferation in a manner similar to intact C1q. The effect of C1q was not cytotoxic but cytostatic since the number of dead cells in the C1q-treated cultures was not significantly different than that in the untreated cells (5% vs 4%), a figure which represents the normal wear and tear of tissue culture conditions. On the basis of these findings we propose that the C1qR alone or in conjunction with other cellular factors may function as a molecule which supports cell growth. Upon ligand binding, however, the ligand-receptor interaction may suppress postreceptor events which are necessary for cell proliferation.

Carrier Proteins↗
PubMed1982

Fluid phase activation of proenzymic C1r purified by affinity chromatography.

1. Proenzymic C1r was purified from human plasma in a two-step technique involving indirect affinity chromatography on Sepharose Ig anti-C1s. The capacity of C1r to monomerize at pH 5.0 and to redimerize at neutral pH was used for selective elution of C1r. The yield in purified C1r was 39% from plasma; no trace of contaminating serine proteases was detected from [3H]diisopropyl phosphorofluoridate labelling of C1r. 2. C14 was able to undergo a two-way autoactivation: an intramolecular catalytic process catalysed by proenzymic C1r itself and an intermolecular reaction catalysed by activated C1r formed in the process of the reaction. DFP (5mM) and C1 Inh at a C1 Inh/C1r ratio of 1:1 were effective on the solely intermolecular activation, leading to partial inhibition of the autoactivation from proenzymic C1r: C1r formed during the activation was titrated by the inhibitors. Calcium, high ionic strength or acid pH decreased C1r activation. The pH effect was characterized by a slowed-down reaction below pH 6.0 and no net influence at values as high as 10.5. The two types of activation developed similarly as a function of pH. 3. Peripheral iodination of C1r revealed differences in label distribution between proenzymic (A chain moiety 48%, B chain moiety 52%) and activated C1r (A chain 20%, B chain 80%). Two different conformational states of C1r were also suggested by 125I-labelling at different temperatures.

Calcium↗
PubMed2005

Hereditary angioedema.

PURPOSE OF REVIEW: Hereditary angioedema is an autosomal-dominant deficiency of C1 inhibitor--a serpin inhibitor of kallikrein, C1r, C1s, factor XII, and plasmin. Quantitative or qualitative deficiency of C1 inhibitor leads to the generation of vasoactive mediators, most likely bradykinin. The clinical syndrome is repeated bouts of nonpruritic, nonpitting edema of the face, larynx, extermities, and intestinal viscera. Recently, investigators, physicians, and industry have demonstrated a renewed interest in the biology and treatment of hereditary angioedema. RECENT FINDINGS: Investigators have generated a C1INH-/- mouse model that has demonstrated the importance of the contact activation system for hereditary angioedema-related vascular permeability. An interactive database of mutations is available electronically. Investigators have continued exploration into mRNA/protein levels. The proceedings of a recent workshop have been impressive in the scope and depth. Clinicians have produced consensus documents and expert reviews. The pharmaceutical industry has initiated clinical trails with novel agents. SUMMARY: Hereditary angioedema is often misdiagnosed and poorly treated. Diagnosis requires careful medical and family history and the measurement of functional C1 inhibitor and C4 levels. Attenuated androgens, anti-fibrinolytics, and C1 inhibitor concentrates are used for long-term and preprocedure prophylaxis, but have significant drawbacks. C1 inhibitor concentrates and fresh frozen plasma are available for acute intervention. The mainstays of supportive care are airway monitoring, pain relief, hydration, and control of nausea. New agents such as recombinant C1 inhibitor, kallikrein inhibitors, and bradykinin inhibitors may offer safer and more tolerable treatments.

Angioedema↗
PubMed1993

Chymotrypsin inhibitory activity of normal C1-inhibitor and a P1 Arg to His mutant: evidence for the presence of overlapping reactive centers.

C1-inhibitor is a serine proteinase inhibitor that is active against C1s, C1r, kallikrein, and factor XII. Recently, it has been shown that it also has inhibitory activity against chymotrypsin. We have investigated this activity of normal human C1-inhibitor, normal rabbit C1-inhibitor, and P1 Arg to His mutant human C1-inhibitors and find that all are able to inhibit chymotrypsin and form stable sodium dodecyl sulfate-resistant complexes. The Kass values show that the P1 His mutant is a slightly better inhibitor of chymotrypsin than normal human C1-inhibitor (3.4 x 10(4) compared with 7.3 x 10(3)). The carboxy-terminal peptide of normal human C1-inhibitor, derived from the dissociated protease-inhibitor complex, shows cleavage between the P2 and P1 residues. Therefore, as with alpha 2-antiplasmin, C1-inhibitor possesses two overlapping P1 residues, one for chymotrypsin and the other for Arg-specific proteinases. In contrast, with the P1 His mutant, the peptide generated from the dissociation of its complex with chymotrypsin demonstrated cleavage between the P1 and P'1 residues. Therefore, unlike alpha 2-antiplasmin, chymotrypsin utilizes the P2 residue as its reactive site in normal C1-inhibitor but utilizes the P1 residue as its reactive site in the P1 His mutant protein. This suggests that the reactive center loop allows a degree of induced fit and therefore must be relatively flexible.

Amino Acid Sequence↗