Inhibition of amyloid fiber assembly by both BiP and its target peptide

Immunoglobulin light chain (LC) normally is a soluble, secreted protein, bu t some LC assemble into ordered fibrils whose deposition in tissues results in amyloidosis and organ failure. Here we reconstitute fibril formation in vitro and show that preformed fibrils can nucleate polymerization of solub le LC. This prion-like behavior has important physiological implications, s ince somatic mutations generate multiple related LC sequences. Furthermore, we demonstrate that fibril formation in vitro and aggregation of whole LC within cells are inhibited by BiP and by a synthetic peptide that is identi cal to a major LC binding site for Sip. We propose that LC form fibrils via an interprotein loop swap and that the underlying conformational change sh ould be amenable to drug therapy.