Cellular mechanism of fibril formation from serum amyloid A1 protein
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- Stephanie Claus
- Institute of Protein Biochemistry Ulm University Ulm Germany
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- Katrin Meinhardt
- Institute of Protein Biochemistry Ulm University Ulm Germany
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- Tobias Aumüller
- Institute of Protein Biochemistry Ulm University Ulm Germany
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- Ioana Puscalau‐Girtu
- Institute of Protein Biochemistry Ulm University Ulm Germany
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- Julia Linder
- Institute of Protein Biochemistry Ulm University Ulm Germany
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- Christian Haupt
- Institute of Protein Biochemistry Ulm University Ulm Germany
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- Paul Walther
- Central Electron Microscopy Facility Ulm University Ulm Germany
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- Tatiana Syrovets
- Institute of Pharmacology of Natural Products & Clinical Pharmacology Ulm University Ulm Germany
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- Thomas Simmet
- Institute of Pharmacology of Natural Products & Clinical Pharmacology Ulm University Ulm Germany
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- Marcus Fändrich
- Institute of Protein Biochemistry Ulm University Ulm Germany
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説明
<jats:title>Abstract</jats:title><jats:p>Serum amyloid A1 (<jats:styled-content style="fixed-case">SAA</jats:styled-content>1) is an apolipoprotein that binds to the high‐density lipoprotein (<jats:styled-content style="fixed-case">HDL</jats:styled-content>) fraction of the serum and constitutes the fibril precursor protein in systemic <jats:styled-content style="fixed-case">AA</jats:styled-content> amyloidosis. We here show that <jats:styled-content style="fixed-case">HDL</jats:styled-content> binding blocks fibril formation from soluble <jats:styled-content style="fixed-case">SAA</jats:styled-content>1 protein, whereas internalization into mononuclear phagocytes leads to the formation of amyloid. <jats:styled-content style="fixed-case">SAA</jats:styled-content>1 aggregation in the cell model disturbs the integrity of vesicular membranes and leads to lysosomal leakage and apoptotic death. The formed amyloid becomes deposited outside the cell where it can seed the fibrillation of extracellular <jats:styled-content style="fixed-case">SAA</jats:styled-content>1. Our data imply that cells are transiently required in the amyloidogenic cascade and promote the initial nucleation of the deposits. This mechanism reconciles previous evidence for the extracellular location of deposits and amyloid precursor protein with observations the cells are crucial for the formation of amyloid.</jats:p>
収録刊行物
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- EMBO reports
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EMBO reports 18 (8), 1352-1366, 2017-06-21
Springer Science and Business Media LLC