Molecular mechanism of amyloidogenic mutations in hypervariable regions of antibody light chains.

ABSTRACT: Systemic light chain (AL) amyloidosis is a fatal protein misfolding disease in which excessive secretion, misfolding, and subsequent aggregation of free antibody light chains eventually lead to deposition of amyloid plaques in various organs. Patient-specific mutations in the antibody V_L domain are closely linked to the disease, but the molecular mechanisms by which certain mutations induce misfolding and amyloid aggregation of antibody domains are still poorly understood. Here, we compare a patient V_L domain with its nonamyloidogenic germline counterpart and show that, out of the five mutations present, two of them strongly destabilize the protein and induce amyloid fibril formation. Surprisingly, the decisive, disease-causing mutations are located in the highly vari

SUBMITTER: Rottenaicher GJ 

PROVIDER: S-EPMC7949129 | biostudies-literature | 2021 Jan-Jun

REPOSITORIES: biostudies-literature