PT  - JOURNAL ARTICLE
AU  - Boris Brumshtein
AU  - Shannon R. Esswein
AU  - Michael R. Sawaya
AU  - Alan T. Ly
AU  - Meytal Landau
AU  - David S. Eisenberg
TI  - Identification of two principal amyloid-driving segments in variable domains of Ig light chains in AL amyloidosis
AID  - 10.1101/354571
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 354571
4099  - http://biorxiv.org/content/early/2018/06/26/354571.short
4100  - http://biorxiv.org/content/early/2018/06/26/354571.full
AB  - 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 β-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.