Identification of two principal amyloid-driving segments in variable domains of Ig light chains in AL amyloidosis
Systemic light chain amyloidosis (AL) is a disease caused by overexpression of monoclonal immunoglobulin light chains that form pathogenic amyloid fibrils. These amyloid fibrils deposit in tissues and cause organ failure. Proteins form amyloid fibrils when they partly or fully unfold and expose segments capable of stacking into {beta}-sheets that pair forming a tight, dehydrated interface. These structures, termed steric zippers, constitute the spines of amyloid fibrils. Here, we identify segments within the variable domains of Ig light chains that drive the assembly of amyloid fibrils in AL. We demonstrate there are at least two such segments. Each one can drive amyloid fibril assembly independently of the other. Thus these two segments are therapeutic targets. In addition to elucidating the molecular pathogenesis of AL, these findings also provide an experimental approach to identify segments that drive fibril formation in other amyloid diseases.