Polymorphic IGLV6-57 AL amyloid fibrils and features of a shared folding pathway

Abstract

Immunoglobulin light chain (AL) amyloidosis is a systemic disorder caused by the misfolding and aggregation of free immunoglobulin light chains (LCs) secreted by abnormal plasma cells. The resulting amyloid fibrils deposit in multiple organs, leading to progressive dysfunction and increased morbidity and mortality. Despite recent advances, the molecular determinants of LC aggregation and phenotypic variability remain poorly understood. Structural characterization of ex-vivo fibrils provides key insights into these pathogenic processes. Here, we report cryo-electron microscopy structures of cardiac AL amyloid fibrils derived from an IGLV6 light chain. The fibrils display two distinct morphologies composed of single and double protofilaments, each adopting a previously unobserved fold. Comparison with previously reported AL fibril structures reveals that while individual mutations can alter the local conformation, IGLV6-derived fibrils share conserved structural motifs that may underlie common aggregation pathways. These findings expand the disease structural landscape and highlight sequence-dependent yet structurally constrained mechanisms of LC fibril formation.