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Naturally Occurring Genetic Variants of Human Caspase-1 Differ Considerably in Structure and the Ability to Activate Interleukin-1beta

Luksch, H and Romanowski, MJ and Chara, O and Tungler, V and Caffarena, ER and Heymann, MC and Lohse, P and Aksentijevich, I and Remmers, EF and Flecks, S and Quoos, N and Gramatte, J and Petzold, C and Hofmann, SR and Winkler, S and Pessler, F and Kallinich, T and Ganser, G and Nimtz-Talaska, A and Baumann, U and Runde, V and Grimbacher, B and Birmelin, J and Gahr, M and Roesler, J and Rosen-Wolff, A (2013) Naturally Occurring Genetic Variants of Human Caspase-1 Differ Considerably in Structure and the Ability to Activate Interleukin-1beta. Human Mutation. pp. 122-131.

Abstract

Caspase-1 (Interleukin-1 Converting Enzyme, ICE) is a proinflammatory enzyme that plays pivotal roles in innate immunity and many inflammatory conditions such as periodic fever syndromes and gout. Inflammation is often mediated by enzymatic activation of interleukin (IL)-1beta and IL-18. We detected seven naturally occurring human CASP1 variants with different effects on protein structure, expression, and enzymatic activity. Most mutations destabilized the caspase-1 dimer interface as revealed by crystal structure analysis and homology modeling followed by molecular dynamics simulations. All variants demonstrated decreased or absent enzymatic and IL-1beta releasing activity in vitro, in a cell transfection model, and as low as 25% of normal ex vivo in a whole blood assay of samples taken from subjects with variant CASP1, a subset of whom suffered from unclassified autoinflammation. We conclude that decreased enzymatic activity of caspase-1 is compatible with normal life and does not prevent moderate and severe autoinflammation. 2012 Wiley Periodicals, Inc

Item Type: Article
Additional Information: pubid: 157 nvp_institute: NIBR contributor_address: (Luksch, Tungler, Heymann, Flecks, Quoos, Gramatte, Petzold, Hofmann, Winkler, Pessler, Gahr, Roesler, Rosen-Wolff) Department of Pediatrics, University Hospital Carl Gustav Carus, Dresden, Germany (Romanowski) Department of Structural Biology, Sunesis Pharmaceuticals, Inc., South San Francisco, CA, United States (Chara) Instituto de Fisica de Fluidos y Sistemas Biologicos (IFLYSIB), CONICET, University of La Plata (UNLP), 59-789 B1900BTE La Plata, Argentina (Chara) Center for Information Services and High-Performance Computing, Technische Universitat Dresden, Dresden, Germany (Caffarena) Programa de Computacao Cientifica, Fundacao Oswaldo Cruz, FIOCRUZ/MS, Manguinhos, Brazil (Lohse) Department of Clinical Chemistry, Ludwig-Maximilians-University, Munich, Germany (Aksentijevich, Remmers) Inflammatory Disease Section, NHGRI, NIH, Bethesda, MD, United States (Pessler) Helmholtz Centre for Infection Research, Braunschweig, Germany (Kallinich) Department for Pediatric Pneumology and Immunology, Charite Medical University of Berlin, Berlin, Germany (Ganser) St. Josef-Stift, Sendenhorst, Germany (Nimtz-Talaska) Kinderrheumatologie, Arztehaus, Frankfurt/Oder, Germany (Baumann) Paediatric Pulmonology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany (Runde) Wilhelm-Anton-Hospital, Goch, Germany (Grimbacher, Birmelin) Centre of Chronic Immunodeficiency, University Hospital Freiburg, Freiburg, Germany (Romanowski) Protein Structure Unit, Novartis Institutes for BioMedical Research, Inc., Cambridge, MA, United States
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12
URI: https://oak.novartis.com/id/eprint/21988

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