Cryo-EM structure of renal AL amyloid fibrils from a patient with λ1 light chain amyloidosis.

Abstract

Systemic light-chain amyloidosis (AL) is characterized by the misfolding and aggregation of immunoglobulin light chains (LCs) into amyloid fibrils, leading to multiorgan deposition and dysfunction, with the kidneys being one of the most commonly involved organs. Here, we report high-resolution cryo-electron microscopy (cryo-EM) structures of AL amyloid fibrils from the kidney of a male patient with renal AL amyloidosis. Two distinct polymorphic fibril structures, polymorph A and polymorph B, were identified, both featuring ordered cores (Gln16-Ser95) with β-sheet-rich architectures stabilized by interchain hydrogen bonds and salt bridges. Notably, six mutations in the IGLV1-44*01 gene sequence, including Gln39His and Tyr37Phe, were identified within the fibril core. These mutations influence fibril stability and aggregation by altering intramolecular and intermolecular interactions, such as CH-π stacking and salt bridge formation. Comparative analysis with previously reported heart-derived IGLV1-44 fibrils reveals structural variations linked to light-chain sequence differences. Our findings provide critical insights into the molecular determinants of fibril assembly and organ tropism in AL amyloidosis.