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

Parker Bassett, Binh A. Nguyen, Virender Singh, Patrick T. Garrett, James J. Moresco, Joshua Eddy, Shumaila Afrin, Maja Pękała, Christian Lopez Escobar, Bret M. Evers, Yasmin Ahmed, Rose Pedretti, Justin L. Grodin, Lori R. Roth, Gurbakhash Kaur, Stephen S. Chung, Gareth J. Morgan, John R. Yates, Lorena Saelices

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 their effect on phenotypic variability are not fully defined. Structural characterization of ex-vivo fibrils provides insights into the underlying amyloidogenic processes that may affect the downstream pathogenesis. Here, we report cryo-electron microscopy structures of cardiac AL amyloid fibrils derived from an IGLV6-57 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, IGLV6-57-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. Researchers use cryogenic electron microscopy to study the unique structure of amyloid fibrils from the heart of a patient with AL amyloidosis. The amyloid fibrils display polymorphic structures, and share some similarities to previously determined structures.