A hinge region mutation in C1-inhibitor (Ala436–>Thr) results in nonsubstrate-like behavior and in polymerization of the molecule

C1-inhibitor(Mo), a dysfunctional C1-inhibitor molecule produced in two kindred with type II hereditary angioedema, has a mutation at the P10 position (Ala436 to Thr). Like most serpins with hinge region mutations (P14, P12, P10), C1-inhibitor(Mo) loses its inhibitory activity. However, unlike the o...

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Bibliographic Details
Published in:The Journal of biological chemistry 1993-08, Vol.268 (24), p.18088-18094
Main Authors: Aulak, K.S., Eldering, E., Hack, C.E., Lubbers, Y.P., Harrison, R.A., Mast, A., Cicardi, M., Davis, A.E.
Format: Article
Language:English
Subjects:
Alanine
Amino Acid Sequence
Analytical, structural and metabolic biochemistry
Animals
Biological and medical sciences
Cell Line
Centrifugation, Density Gradient
Chromatography, Gel
Cloning, Molecular
Complement C1 Inactivator Proteins - chemistry
Complement C1 Inactivator Proteins - genetics
Complement C1 Inactivator Proteins - isolation & purification
Drug Stability
Electrophoresis, Polyacrylamide Gel
Enzymes and enzyme inhibitors
Fundamental and applied biological sciences. Psychology
Humans
Hydrolases
Microscopy, Electron
Point Mutation
Protein Denaturation
Thermodynamics
Threonine
Transfection
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Summary:C1-inhibitor(Mo), a dysfunctional C1-inhibitor molecule produced in two kindred with type II hereditary angioedema, has a mutation at the P10 position (Ala436 to Thr). Like most serpins with hinge region mutations (P14, P12, P10), C1-inhibitor(Mo) loses its inhibitory activity. However, unlike the other hinge region mutations, this mutant is not converted to a substrate. As shown by nondenaturing gel electrophoresis, gel filtration, sucrose density gradient ultracentrifugation, and electron microscopy, C1-inhibitor(Mo) exists in both monomeric and multimeric forms. Polymerization probably results from reactive center loop insertion into the A sheet of an adjacent molecule. Native C1-inhibitor(Mo) was shown to have a thermal stability profile intermediate to those of intact and of cleaved normal C1-inhibitor. Native C1-inhibitor(Mo) did not bind to monoclonal antibody KII, which binds only to reactive center-cleaved normal C1-inhibitor. It did, however, react with monoclonal antibody KOK12, which recognizes complexed or cleaved C1-inhibitor but not intact normal C1-inhibitor. Native C1-inhibitor(Mo), therefore, exists in a conformation similar to the complexed form of normal C1-inhibitor.
ISSN:0021-9258
1083-351X
DOI:10.1016/S0021-9258(17)46815-3