NR ADBO
AU Davis,P.D.; Raffen,R.; Dul,L.J.; Vogen,M.S.; Williamson,K.E.; Stevens,J.F.; Argon,Y.
TI Inhibition of amyloid fiber assembly by both BiP and its target peptide
QU Immunity 2000 Oct; 13(4): 433-42
PT journal article
AB Immunoglobulin light chain (LC) normally is a soluble, secreted protein, but 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 soluble LC. This prion-like behavior has important physiological implications, since 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 identical to a major LC binding site for BiP. We propose that LC form fibrils via an interprotein loop swap and that the underlying conformational change should be amenable to drug therapy.
MH Amino Acid Sequence; Amino Acid Substitution/genetics; Amyloid/*antagonists & inhibitors/biosynthesis/genetics/*metabolism; Amyloidosis/genetics/immunology; Animal; COS Cells; Carrier Proteins/biosynthesis/genetics/metabolism/*physiology; Human; Immunoglobulin Variable Region/genetics/metabolism/physiology; Immunoglobulins, Light-Chain/genetics/*metabolism/physiology; Mice; Microfibrils/metabolism; Molecular Chaperones/biosynthesis/genetics/metabolism/*physiology; Molecular Sequence Data; Muscle, Smooth/metabolism; Mutagenesis, Site-Directed; Oligopeptides/metabolism/physiology; Peptide Fragments/metabolism/*physiology; Solubility; Support, Non-U.S. Gov't; Support, U.S. Gov't, Non-P.H.S.; Support, U.S. Gov't, P.H.S.
AD Department of Pathology and Committee on Immunology, The University of Chicago, Illinois 60637, USA
SP englisch
PO USA