The AL Amyloid Fibril: Looking for a Link between Fibril Formation and Structure
Christian Haupt
- Vol. 2, Iss: 3, pp 505-514
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TLDR
Recent biochemical and biophysical studies that have expanded knowledge on how versatile the structure of AL fibrils in patients is are reviewed and highlighted their implications for the molecular mechanism of fibril formation in AL amyloidosis are highlighted.Abstract:
The formation and deposition of fibrils derived from immunglobulin light chains is a hallmark of systemic AL amyloidosis. A particularly remarkable feature of the disease is the diversity and complexity in pathophysiology and clinical manifestations. This is related to the variability of immunoglobulins, as virtually every patient has a variety of mutations resulting in their own unique AL protein and thus a unique fibril deposited in the body. Here, I review recent biochemical and biophysical studies that have expanded our knowledge on how versatile the structure of AL fibrils in patients is and highlight their implications for the molecular mechanism of fibril formation in AL amyloidosis.read more
Citations
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Transient disorder along pathways to amyloid
TL;DR: In this article, high-resolution structures of amyloid fibrils formed from normally-folded proteins have revealed non-native conformations of the polypeptide chains, in contrast to earlier models that posited a role for assembly of partially folded proteins.
Journal ArticleDOI
Concurrent light chain amyloidosis and proximal tubulopathy: Insights into different aggregation behavior—A case report
Simone Feurstein,Julian Zoller,Constantin Schwab,S. Schreiner,Heiko M. Mundt,Iris Breitkreutz,Brigitte Schneider,Jörg Beimler,Martin Zeier,Rüdiger Waldherr,Stefan Gröschel,Carsten Müller-Tidow,Stefan Schönland,Ute Hegenbart +13 more
TL;DR: In this paper , the first case of concurrent AL amyloidosis and a subclass of MGRS, light chain proximal tubulopathy (LCPT), was reported in a 53-year-old female with smoldering myeloma immunoglobulin G kappa.
References
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Journal ArticleDOI
Cryo-EM structure of a light chain-derived amyloid fibril from a patient with systemic AL amyloidosis
Lynn Radamaker,Yin-Hsi Lin,Karthikeyan Annamalai,Stefanie Huhn,Ute Hegenbart,Stefan Schönland,Günter Fritz,Günter Fritz,Matthias Schmidt,Marcus Fändrich +9 more
TL;DR: The structure of a λ1 AL amyloid fibril from an explanted human heart at a resolution of 3.3 Å provides insight into the mechanism of protein misfolding and the role of patient-specific mutations in pathogenicity.
Journal ArticleDOI
Altered Dimer Interface Decreases Stability in an Amyloidogenic Protein
Elizabeth M. Baden,Barbara A.L. Owen,Francis C. Peterson,Brian F. Volkman,Marina Ramirez-Alvarado,James R. Thompson +5 more
TL;DR: The notion that the increased stability of the monomer and delayed fibril formation, together with a properly formed dimer, may be protective against amyloidogenesis could open a new direction into rational drug design for amyloidsogenic proteins.
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Four structural risk factors identify most fibril-forming kappa light chains
TL;DR: It is suggested that it is feasible to predict fibril propensity by analysis of primary structure of antibody LCs, and this study focuses on amyloidogenesis within the Kl family of human LCs.
Journal ArticleDOI
Polymorphism of Amyloid Fibrils In Vivo
Karthikeyan Annamalai,Karl-Heinz Gührs,Rolf Koehler,Matthias Schmidt,Henri Michel,Cornelia Loos,Patricia M. Gaffney,Christina J. Sigurdson,Ute Hegenbart,Stefan Schönland,Marcus Fändrich +10 more
TL;DR: It is shown that the amyloid fibrils within a diseased individual can vary considerably in their three-dimensional architecture, which implies that the chemical principles of fibril assembly that lead to such polymorphism are fundamentally conserved in’vivo and in vitro.
Journal ArticleDOI
Clarifying immunoglobulin gene usage in systemic and localized immunoglobulin light-chain amyloidosis by mass spectrometry
Taxiarchis Kourelis,Surendra Dasari,Jason D. Theis,Marina Ramirez-Alvarado,Paul J. Kurtin,Morie A. Gertz,Steven R. Zeldenrust,Roman M. Zenka,Ahmet Dogan,Angela Dispenzieri +9 more
TL;DR: Investigating the frequency of use of light-chain variable region (IGVL) genes among patients with systemic (ALS) and localized (ALL) amyloidosis and to assess for associations between IGVL gene usage and organ tropism found them to provide clues about disease pathophysiology and tissue tropism.