Fatal amyloid formation in a patient’s antibody light chain is caused by a single point mutation
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- Pamina Kazman
- Center for Integrated Protein Science Munich at the Department Chemie, Technische Universität München, Garching, Germany
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- Marie-Theres Vielberg
- Center for Integrated Protein Science Munich at the Department Chemie, Technische Universität München, Garching, Germany
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- María Daniela Pulido Cendales
- Center for Integrated Protein Science Munich at the Department Physik, Technische Universität München, Garching, Germany
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- Lioba Hunziger
- Center for Integrated Protein Science Munich at the Department Chemie, Technische Universität München, Garching, Germany
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- Benedikt Weber
- Center for Integrated Protein Science Munich at the Department Chemie, Technische Universität München, Garching, Germany
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- Ute Hegenbart
- Medical Department V, Amyloidosis Center, University of Heidelberg, Heidelberg, Germany
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- Martin Zacharias
- Center for Integrated Protein Science Munich at the Department Physik, Technische Universität München, Garching, Germany
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- Rolf Köhler
- Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany
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- Stefan Schönland
- Medical Department V, Amyloidosis Center, University of Heidelberg, Heidelberg, Germany
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- Michael Groll
- Center for Integrated Protein Science Munich at the Department Chemie, Technische Universität München, Garching, Germany
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- Johannes Buchner
- Center for Integrated Protein Science Munich at the Department Chemie, Technische Universität München, Garching, Germany
抄録
<jats:p>In systemic light chain amyloidosis, an overexpressed antibody light chain (LC) forms fibrils which deposit in organs and cause their failure. While it is well-established that mutations in the LC’s VL domain are important prerequisites, the mechanisms which render a patient LC amyloidogenic are ill-defined. In this study, we performed an in-depth analysis of the factors and mutations responsible for the pathogenic transformation of a patient-derived λ LC, by recombinantly expressing variants in E. coli. We show that proteolytic cleavage of the patient LC resulting in an isolated VL domain is essential for fibril formation. Out of 11 mutations in the patient VL, only one, a leucine to valine mutation, is responsible for fibril formation. It disrupts a hydrophobic network rendering the C-terminal segment of VL more dynamic and decreasing domain stability. Thus, the combination of proteolytic cleavage and the destabilizing mutation trigger conformational changes that turn the LC pathogenic.</jats:p>
収録刊行物
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- eLife
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eLife 9 2020-03-10
eLife Sciences Publications, Ltd