Version 1
: Received: 17 October 2024 / Approved: 17 October 2024 / Online: 17 October 2024 (17:08:50 CEST)
How to cite:
Morgan, G. J.; Yung, Z.; Spencer, B. H.; Sanchorawala, V.; Prokaeva, T. Structural Consequences of Antibody Light Chain N Glycosylation in AL Amyloidosis. Preprints2024, 2024101407. https://doi.org/10.20944/preprints202410.1407.v1
Morgan, G. J.; Yung, Z.; Spencer, B. H.; Sanchorawala, V.; Prokaeva, T. Structural Consequences of Antibody Light Chain N Glycosylation in AL Amyloidosis. Preprints 2024, 2024101407. https://doi.org/10.20944/preprints202410.1407.v1
Morgan, G. J.; Yung, Z.; Spencer, B. H.; Sanchorawala, V.; Prokaeva, T. Structural Consequences of Antibody Light Chain N Glycosylation in AL Amyloidosis. Preprints2024, 2024101407. https://doi.org/10.20944/preprints202410.1407.v1
APA Style
Morgan, G. J., Yung, Z., Spencer, B. H., Sanchorawala, V., & Prokaeva, T. (2024). Structural Consequences of Antibody Light Chain N Glycosylation in AL Amyloidosis. Preprints. https://doi.org/10.20944/preprints202410.1407.v1
Chicago/Turabian Style
Morgan, G. J., Vaishali Sanchorawala and Tatiana Prokaeva. 2024 "Structural Consequences of Antibody Light Chain N Glycosylation in AL Amyloidosis" Preprints. https://doi.org/10.20944/preprints202410.1407.v1
Abstract
Antibody light chains form amyloid fibrils that lead to progressive tissue damage in amyloid light chain (AL) amyloidosis. The properties of each patient’s unique light chain appear to determine its propensity to form amyloid. One factor is N-glycosylation, which is more frequent in amyloid-associated light chains than in light chains from the normal immune repertoire. However, the mechanisms underlying this association are unknown. Here, we investigate the frequency and position within the light chain sequence of the N-glycosylation sequence motif, or sequon. Monoclonal light chains from AL amyloidosis and multiple myeloma were identified from the AL-Base repository. Polyclonal light chains were obtained from the Observed Antibody Space resource. Sequons are enriched among AL-associated light chains derived from a subset of precursor germline genes. Sequons are observed at multiple positions, which differ between the two types of light chains, κ and λ, but are similar between light chains from AL amyloidosis and multiple myeloma. Positions of sequons map to residues with surface-exposed sidechains that are compatible with the folded structures of light chains. Sequons within κ light chains are predominantly observed in framework region 3. Sequons within λ light chains are mainly located in complementarity determining region 3, at residues near the interfaces with light or heavy chain partners in homodimeric free light chains or antibodies, respectively. We suggest that N-glycosylation of λ light chains may lead to decreased stability of protein complexes, thus promoting unfolding that can lead to aggregation. Within the known structures of λ AL amyloid fibrils, many residues where sequons are observed are buried, inconsistent with N-glycosylation. Overall, there is no clear structural rationale for why N-glycosylation of κ light chains is associated with amyloidosis. Better understanding of the roles of N-glycosylation in AL amyloidosis is required before it can be used as a marker for disease risk.
Keywords
Light chain amyloidosis; immunoglobulin; systemic amyloid disease; N-glycosylation; sequon; amyloid fibrils; protein misfolding; protein aggregation
Subject
Biology and Life Sciences, Biochemistry and Molecular Biology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
