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Weber, B.* ; Hora, M.* ; Kazman, P.* ; Göbl, C. ; Camilloni, C.* ; Reif, B.* ; Buchner, J.*

The antibody light-chain linker regulates domain orientation and amyloidogenicity.

J. Mol. Biol. 430, 4925-4940 (2018)
Postprint DOI PMC
Open Access Green
The antibody light chain (LC) consists of two domains and is essential for antigen binding in mature immunoglobulins. The two domains are connected by a highly conserved linker that comprises the structurally important Arg108 residue. In antibody light chain (AL) amyloidosis, a severe protein amyloid disease, the LC and its N-terminal variable domain (V-L) convert to fibrils deposited in the tissues causing organ failure. Understanding the factors shaping the architecture of the LC is important for basic science, biotechnology and for deciphering the principles that lead to fibril formation. In this study, we examined the structure and properties of LC variants with a mutated or extended linker. We show that under destabilizing conditions, the linker modulates the amyloidogenicity of the LC. The fibril formation propensity of LC linker variants and their susceptibility to proteolysis directly correlate implying an interplay between the two LC domains. Using NMR and residual dipolar coupling-based simulations, we found that the linker residue Arg108 is a key factor regulating the relative orientation of the VL and CL domains, keeping them in a bent and dense, but still flexible conformation. Thus, inter-domain contacts and the relative orientation of VL and CL to each other are of major importance for maintaining the structural integrity of the full-length LC. (C) 2018 Elsevier Ltd. All rights reserved.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Antibody Folding ; Protein Stability ; Light Chain Linker ; Amyloid ; Intramolecular Interactions; Bence-jones Proteins; Amyloid Fibrils; Stability; Conformations; Aggregation; Fragment; Model; Fibrillation; Mechanism; Insight
ISSN (print) / ISBN 0022-2836
e-ISSN 1089-8638
Journal Journal of Molecular Biology
Quellenangaben Volume: 430, Issue: 24, Pages: 4925-4940 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place 24-28 Oval Rd, London Nw1 7dx, England
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Structural Biology (STB)