A Substantial Structural Conversion of the Native Monomer Leads to in‐Register Parallel Amyloid Fibril Formation in Light‐Chain Amyloidosis

Lecoq, Lauriane; Wiegand, Thomas; Rodríguez-Álvarez, Francisco J.; Cadalbert, Riccardo; Herrera, Guillermo A.; Pozo‐Yauner, Luis del; Meier, Beat H.; Böckmann, Anja

doi:10.1002/cbic.201800732

Cited by 23 publications

(35 citation statements)

References 45 publications

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“…Their chemical shifts are typical for cysteines in the oxidized state. This finding is in agreement with an intact disulfide bond in both the two recent cryo-EM structures and the chemical shifts of 6aJL2_R25G fibrils (Lecoq et al 2019;Radamaker et al 2019;Swuec et al 2019).…”

Section: Assignment and Data Depositionsupporting

confidence: 89%

Solid state NMR assignments of a human λ-III immunoglobulin light chain amyloid fibril

et al. 2020

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The aggregation of antibody light chains is linked to systemic light chain (AL) amyloidosis, a disease where amyloid deposits frequently affect the heart and the kidney. We here investigate fibrils from the λ-III FOR005 light chain (LC), which is derived from an AL-patient with severe cardiac involvement. In FOR005, five residues are mutated with respect to its closest germline gene segment IGLV3-19 and IGLJ3. All mutations are located close to the complementarity determining regions (CDRs). The sequence segments responsible for the fibril formation are not yet known. We use fibrils extracted from the heart of this particular amyloidosis patient as seeds to prepare fibrils for solid-state NMR. We show that the seeds induce the formation of a specific fibril structure from the biochemically produced protein. We have assigned the fibril core region of the FOR005-derived fibrils and characterized the secondary structure propensity of the observed amino acids. As the primary structure of the aggregated patient protein is different for every AL patient, it is important to study, analyze and report a greater number of light chain sequences associated with AL amyloidosis.

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Section: Assignment and Data Depositionsupporting

confidence: 89%

Solid state NMR assignments of a human λ-III immunoglobulin light chain amyloid fibril

et al. 2020

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“…21 ), as well as human λ3 (ref. 22 ) and λ6 sequences 23 . Particularly relevant in this case is the comparison of our structures to the NMR analysis of recombinant FOR005 V L domain fibrils 22 .…”

Section: Discussionmentioning

confidence: 99%

Cryo-EM reveals structural breaks in a patient-derived amyloid fibril from systemic AL amyloidosis

et al. 2021

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Systemic AL amyloidosis is a debilitating and potentially fatal disease that arises from the misfolding and fibrillation of immunoglobulin light chains (LCs). The disease is patient-specific with essentially each patient possessing a unique LC sequence. In this study, we present two ex vivo fibril structures of a λ3 LC. The fibrils were extracted from the explanted heart of a patient (FOR005) and consist of 115-residue fibril proteins, mainly from the LC variable domain. The fibril structures imply that a 180° rotation around the disulfide bond and a major unfolding step are necessary for fibrils to form. The two fibril structures show highly similar fibril protein folds, differing in only a 12-residue segment. Remarkably, the two structures do not represent separate fibril morphologies, as they can co-exist at different z-axial positions within the same fibril. Our data imply the presence of structural breaks at the interface of the two structural forms.

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“…Our structures also differ from a number of studies which used nuclear magnetic resonance (NMR) spectroscopy to investigate the structure of LC-derived fibrils formed in vitro. These fibrils were formed from V L domain constructs and include murine κ [20], human κ1 [21] as well as human λ3 [22] and λ6 sequences 23 . Particularly relevant in this case is the comparison of our structures to the NMR analysis of recombinant FOR005 V L domain fibrils 22 .…”

Section: Discussionmentioning

confidence: 99%

Cryo-EM reveals structural breaks in a patient-derived amyloid fibril from systemic AL amyloidosis

Radamaker¹,

Baur

Huhn

et al. 2020

Preprint

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Systemic AL amyloidosis is a debilitating and potentially fatal disease that arises from the misfolding and fibrillation of immunoglobulin light chains (LCs). The disease is patient-specific with essentially each patient possessing a unique LC sequence. In this study, we present the first ex vivo fibril structures of a λ3 LC. The fibrils were extracted from the explanted heart of a patient (FOR005) and consist of 115 residues, mainly from the LC variable domain. The fibril structures imply that a 180° rotation around the disulfide bond and a major unfolding step are necessary for fibrils to form. The two fibril structures show highly similar fibril protein folds, differing in only a 12-residue segment. Remarkably, the two structures do not represent separate fibril morphologies, as they can co-exist at different z-axial positions within the same fibril. Our data imply the presence of structural breaks at the interface of the two structural forms.

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A Substantial Structural Conversion of the Native Monomer Leads to in‐Register Parallel Amyloid Fibril Formation in Light‐Chain Amyloidosis

Cited by 23 publications

References 45 publications

Solid state NMR assignments of a human λ-III immunoglobulin light chain amyloid fibril

Solid state NMR assignments of a human λ-III immunoglobulin light chain amyloid fibril

Cryo-EM reveals structural breaks in a patient-derived amyloid fibril from systemic AL amyloidosis

Cryo-EM reveals structural breaks in a patient-derived amyloid fibril from systemic AL amyloidosis

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