Structural analysis of the amyloidogenic k Bence Jones protein (FUR)

Abstract

Patients with systemic amyloidosis associated with multiple myeloma (AL-amyloidosis) exhibit immunoglobulin light chains and fragments which have been identified as amyloid protein. Since a relatively small proportion of patients with multiple myeloma develop AL-amyloidosis, comparison of the amino acid sequence of the amyloidogenic and non-amyloidogenic immunoglobulin light chains and the structural characterization of the amyloid proteins are required to understand the relationship between structure and amyloidogenicity. We determined the primary structure of a k I-type Bence Jones protein obtained from a patient (FUR) who had systemic AL-amyloidosis associated with multiple myeloma. We identified eight amino acid replacements unique to this patient among the amyloidogenic k I-light chains, and which are also rare among the known K type light chains of humans. Three of these substitutions were within the framework regions and may act to destabilize the structure to promote a putative amyloidogenic conformation. In contrast to light chain fragments in the urine, which were processed in the variable region, mass spectro-metric analysis of the fibril proteins isolated from lingual amyloid deposits in this patient, revealed that they were all truncated within the constant region and corresponded to residues 1-125, 1-144, and 1-210. Inspection of the predicted three-dimensional model of this protein suggested that these fragments may be generated by a protease specific for the N-terminal sides of basic amino acids. These findings suggest that amino acid substitutions at highly conserved residues may convert non-amyloidogenic to amyloidogenic immunoglobulin light chain proteins.