The functional integrity of the serpin domain of C1-inhibitor depends on the unique N-terminal domain, as revealed by a pathological mutant

Bos, Ineke G. A. and Lubbers, Yvonne T. P. and Roem, Dorina and Abrahams, Jan Pieter and Hack, C. Erik and Eldering, Eric. (2003) The functional integrity of the serpin domain of C1-inhibitor depends on the unique N-terminal domain, as revealed by a pathological mutant. Journal of Biological Chemistry, 278 (32). pp. 29463-29470.

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C1-inhibitor (C1-Inh) is a serine protease inhibitor ( serpin) with a unique, non-conserved N-terminal domain of unknown function. Genetic deficiency of C1-Inh causes hereditary angioedema. A novel type of mutation (Delta3) in exon 3 of the C1-Inh gene, resulting in deletion of Asp(62)-Thr(116) in this unique domain, was encountered in a hereditary angioedema pedigree. Because the domain is supposedly not essential for inhibitory activity, the unexpected loss-of-function of this deletion mutant was further investigated. The Delta3 mutant and three additional mutants starting at Pro(76), Gly(98), and Ser(115), lacking increasing parts of the N-terminal domain, were produced recombinantly. C1-Inh(76) and C1-Inh(98) retained normal conformation and interaction kinetics with target proteases. In contrast, C1-Inh(115) and Delta3, which both lack the connection between the serpin and the nonserpin domain via two disulfide bridges, were completely non-functional because of a complex-like and multimeric conformation, as demonstrated by several criteria. The Delta3 mutant also circulated in multimeric form in plasma from affected family members. The C1-Inh mutant reported here is unique in that deletion of an entire amino acid stretch from a domain not shared by other serpins leads to a loss-of-function. The deletion in the unique N-terminal domain results in a "multimerization phenotype" of C1-Inh, because of diminished stability of the central beta-sheet. This phenotype, as well as the location of the disulfide bridges between the serpin and the non-serpin domain of C1-Inh, suggests that the function of the N-terminal region may be similar to one of the effects of heparin in antithrombin III, maintenance of the metastable serpin conformation.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Structural Biology & Biophysics > Nano-diffraction of Biological Specimen (Abrahams)
UniBasel Contributors:Abrahams, Jan Pieter
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Society for Biochemistry and Molecular Biology
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:05 Nov 2020 15:49
Deposited On:05 Nov 2020 15:49

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