Intermittent C1-Inhibitor Deficiency Associated with Recessive Inheritance: Functional and Structural Insight
| Autor: | Romina Berardelli, Silvia Berra, Chiara Suffritti, Marco Cicardi, Annamaria Fra, Sonia Caccia, Vincenzo Martorana, Christian Drouet, Thomas Carzaniga |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Heredity Mutant lcsh:Medicine Complement C1 Inactivator Proteins Serpin Gene mutation KeyWords Plus:HEREDITARY ANGIONEUROTIC-EDEMA C1 INHIBITOR GENE ALPHA(1)-ANTITRYPSIN DEFICIENCY ANGIOEDEMA ATTACKS MOLECULAR-BASIS CL-INHIBITOR IN-VIVO MUTATION POLYMERIZATION POLYMERS Article 03 medical and health sciences 0302 clinical medicine medicine Humans Protein oligomerization Denaturation (biochemistry) Secretion Angioedema lcsh:Science Serine protease Multidisciplinary biology Chemistry lcsh:R Middle Aged medicine.disease Cell biology 030104 developmental biology 030220 oncology & carcinogenesis Mutation Hereditary angioedema biology.protein Female lcsh:Q |
| Zdroj: | Scientific Reports, Vol 8, Iss 1, Pp 1-14 (2018) Scientific Reports Scientific reports (Nature Publishing Group) 8 (2018). doi:10.1038/s41598-017-16667-w info:cnr-pdr/source/autori:Caccia S, Suffritti C, Carzaniga T, Berardelli R, Berra S, Martorana V, Fra A, Drouet C, Cicardi M/titolo:Intermittent C1-Inhibitor Deficiency Associated with Recessive Inheritance: Functional and Structural Insight/doi:10.1038%2Fs41598-017-16667-w/rivista:Scientific reports (Nature Publishing Group)/anno:2018/pagina_da:/pagina_a:/intervallo_pagine:/volume:8 |
| DOI: | 10.1038/s41598-017-16667-w |
| Popis: | C1-inhibitor is a serine protease inhibitor (serpin) controlling complement and contact system activation. Gene mutations result in reduced C1-inhibitor functional plasma level causing hereditary angioedema, a life-threatening disorder. Despite a stable defect, the clinical expression of hereditary angioedema is unpredictable, and the molecular mechanism underlying this variability remains undisclosed. Here we report functional and structural studies on the Arg378Cys C1-inhibitor mutant found in a patient presenting reduced C1-inhibitor levels, episodically undergoing normalization. Expression studies resulted in a drop in mutant C1-innhibitor secretion compared to wild-type. Notwithstanding, the purified proteins had similar features. Thermal denaturation experiments showed a comparable denaturation profile, but the mutant thermal stability decays when tested in conditions reproducing intracellular crowding.Our findings suggest that once correctly folded, the Arg378Cys C1-inhibitor is secreted as an active, although quite unstable, monomer. However, it could bear a folding defect, occasionally promoting protein oligomerization and interfering with the secretion process, thus accounting for its plasma level variability. This defect is exacerbated by the nature of the mutation since the acquired cysteine leads to the formation of non-functional homodimers through inter-molecular disulphide bonding. All the proposed phenomena could be modulated by specific environmental conditions, rendering this mutant exceptionally vulnerable to mild stress. |
| Databáze: | OpenAIRE |
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