Immunoglobulin light chain (AL) amyloidosis is caused by a small, minimally proliferating B-cell/plasma-cell clone secreting a patient-unique, aggregation-prone, toxic light chain (LC). The pathogenicity of LCs is encrypted in their sequence, yet molecular determinants of amyloidogenesis are poorly understood. Higher rates of N-glycosylation among clonal κ LCs from patients with AL amyloidosis compared to other monoclonal gammopathies indicate that this post-translational modification is associated with a higher risk of developing AL amyloidosis. Here, we exploited LC sequence information from previously published amyloidogenic and control clonal LCs and from a series of 220 patients with AL amyloidosis or multiple myeloma followed at our Institutions to define sequence and spatial features of N-glycosylation, combining bioinformatics, biochemical, proteomics, structural and genetic analyses. We found peculiar sequence and spatial pattern of N-glycosylation in amyloidogenic κ LCs, with most of the N-glycosylation sites laying in the framework region 3, particularly within the E strand, and consisting mainly of the NFT sequon, setting them apart with respect to non-amyloidogenic clonal LCs. Our data further support a potential role of N-glycosylation in determining the pathogenic behavior of a subset of amyloidogenic LCs and may help refine current N-glycosylation-based prognostic assessments for patients with monoclonal gammopathies.

An N-glycosylation hotspot in immunoglobulin κ light chains is associated with AL amyloidosis / A. Nevone, M. Girelli, S. Mangiacavalli, B. Paiva, P. Milani, P. Cascino, M. Piscitelli, V. Speranzini, C.S. Cartia, P. Benvenuti, I. Goicoechea, F. Fazio, M. Basset, A. Foli, M. Nanci, G. Mazzini, S. Caminito, M.A. Sesta, S. Casarini, P. Rognoni, F. Lavatelli, M.T. Petrucci, P.P. Olimpieri, S. Ricagno, L. Arcaini, G. Merlini, G. Palladini, M. Nuvolone. - In: LEUKEMIA. - ISSN 0887-6924. - (2022). [Epub ahead of print] [10.1038/s41375-022-01599-w]

An N-glycosylation hotspot in immunoglobulin κ light chains is associated with AL amyloidosis

Speranzini, Valentina;Ricagno, Stefano;
2022

Abstract

Immunoglobulin light chain (AL) amyloidosis is caused by a small, minimally proliferating B-cell/plasma-cell clone secreting a patient-unique, aggregation-prone, toxic light chain (LC). The pathogenicity of LCs is encrypted in their sequence, yet molecular determinants of amyloidogenesis are poorly understood. Higher rates of N-glycosylation among clonal κ LCs from patients with AL amyloidosis compared to other monoclonal gammopathies indicate that this post-translational modification is associated with a higher risk of developing AL amyloidosis. Here, we exploited LC sequence information from previously published amyloidogenic and control clonal LCs and from a series of 220 patients with AL amyloidosis or multiple myeloma followed at our Institutions to define sequence and spatial features of N-glycosylation, combining bioinformatics, biochemical, proteomics, structural and genetic analyses. We found peculiar sequence and spatial pattern of N-glycosylation in amyloidogenic κ LCs, with most of the N-glycosylation sites laying in the framework region 3, particularly within the E strand, and consisting mainly of the NFT sequon, setting them apart with respect to non-amyloidogenic clonal LCs. Our data further support a potential role of N-glycosylation in determining the pathogenic behavior of a subset of amyloidogenic LCs and may help refine current N-glycosylation-based prognostic assessments for patients with monoclonal gammopathies.
Settore BIO/10 - Biochimica
24-mag-2022
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/929232
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