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  Dissection of the amyloid formation pathway in AL amyloidosis

Kazman, P., Absmeier, R. M., Engelhardt, H., & Buchner, J. (2021). Dissection of the amyloid formation pathway in AL amyloidosis. Nature Communications, 12(1): 6516. doi:10.1038/s41467-021-26845-0.

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 Creators:
Kazman, Pamina1, Author
Absmeier, Ramona M.1, Author
Engelhardt, Harald2, Author              
Buchner, Johannes1, Author
Affiliations:
1external, ou_persistent22              
2Baumeister, Wolfgang / Molecular Structural Biology, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565142              

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Free keywords: LIGHT-CHAIN AMYLOIDOSIS; FIBRIL FORMATION; BETA-PROTEIN; STABILITY; FRAGMENT; HYDROPHOBICITY; ACRYLAMIDE; MECHANISM; SPECTRA; MODELScience & Technology - Other Topics;
 Abstract: In antibody light chain (AL) amyloidosis, overproduced light chain (LC) fragments accumulate as fibrils in organs and tissues of patients. In vitro, AL fibril formation is a slow process, characterized by a pronounced lag phase. The events occurring during this lag phase are largely unknown. We have dissected the lag phase of a patient-derived LC truncation and identified structural transitions that precede fibril formation. The process starts with partial unfolding of the V-L domain and the formation of small amounts of dimers. This is a prerequisite for the formation of an ensemble of oligomers, which are the precursors of fibrils. During oligomerization, the hydrophobic core of the LC domain rearranges which leads to changes in solvent accessibility and rigidity. Structural transitions from an anti-parallel to a parallel beta-sheet secondary structure occur in the oligomers prior to amyloid formation. Together, our results reveal a rate-limiting multi-step mechanism of structural transitions prior to fibril formation in AL amyloidosis, which offers, in the long run, opportunities for therapeutic intervention. AL amyloidosis is caused by the accumulation of overproduced light chain (LC) fragments as fibrils in patient organs and it is the most prevalent systemic amyloidosis. Here, the authors combine biochemical and biophysical experiments to characterise the lag phase of a patient-derived truncated LC and they identify structural transitions that precede fibril formation.

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Language(s): eng - English
 Dates: 2021-11
 Publication Status: Published online
 Pages: 10
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 Table of Contents: -
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Title: Nature Communications
  Abbreviation : Nat. Commun.
Source Genre: Journal
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Publ. Info: London : Nature Publishing Group
Pages: - Volume / Issue: 12 (1) Sequence Number: 6516 Start / End Page: - Identifier: ISSN: 2041-1723
CoNE: https://pure.mpg.de/cone/journals/resource/2041-1723