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Pradhan, T. ; Sarkar, R. ; Meighen-Berger, K.M.* ; Feige, M.J.* ; Zacharias, M.* ; Reif, B.

Mechanistic insights into the aggregation pathway of the patient-derived immunoglobulin light chain variable domain protein FOR005.

Nat. Commun. 14:3755 (2023)

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Systemic antibody light chain (AL) amyloidosis is characterized by deposition of amyloid fibrils. Prior to fibril formation, soluble oligomeric AL protein has a direct cytotoxic effect on cardiomyocytes. We focus on the patient derived λ-III AL variable domain FOR005 which is mutated at five positions with respect to the closest germline protein. Using solution-state NMR spectroscopy, we follow the individual steps involved in protein misfolding from the native to the amyloid fibril state. Unfavorable mutations in the complementary determining regions introduce a strain in the native protein structure which yields partial unfolding. Driven by electrostatic interactions, the protein converts into a high molecular weight, oligomeric, molten globule. The high local concentration of aggregation prone regions in the oligomer finally catalyzes the conversion into fibrils. The topology is determined by balanced electrostatic interactions in the fibril core implying a 180° rotational switch of the beta-sheets around the conserved disulfide bond.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Amyloid Fibrillation; Hydrogen-exchange; Amyloidogenicity; Spectroscopy; Equilibrium; Dependence; Dynamics; Fibrils; Phase; Ph

ISSN (print) / ISBN 2041-1723

e-ISSN 2041-1723

Journal Nature Communications

Quellenangaben Volume: 14, Issue: 1, Article Number: 3755

Publisher Nature Publishing Group

Publishing Place London

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Structural Biology (STB)

Grants Projekt DEAL
Helmholtz-Gemeinschaft
project SP04)
Research Unit FOR 2969 (German Research Foundation DFG