Multifaceted effects of N-glycosylation on amyloidogenic κ light chains in AL amyloidosis

Abstract

Light chain (LC) amyloidosis (AL) is a fatal disorder caused by extracellular aggregation of monoclonal immunoglobulin LCs. While both λ and κ isotypes can be involved, κ-LCs account for only ∼20% of cases, and their aggregation mechanisms remain less understood. Recent evidence suggests that N-glycosylation influences κ-LC aggregation and is strongly linked to AL amyloidosis. To investigate this, we examined patient-derived κ-LCs in both glycosylated and unglycosylated forms. Mass spectrometry confirmed the presence of complex-type N-glycans. Biophysical analyses showed that glycosylation enhances structural compactness, stabilizes the native structure, and promotes cooperative unfolding. Glycosylated κ-LCs also exhibited reduced conformational dynamics. Functionally, N-glycosylation significantly improved LC secretion efficiency and extracellular stability. These findings suggest that N-glycosylation acts as a protective factor against amyloid formation and enhances LC accumulation outside the cell. Overall, our study highlights the multifaceted and context-dependent role of N-glycosylation in modulating κ-LC behavior, with important implications in AL pathogenesis.