pH-dependent fibrillogenesis of a V kappa III Bence Jones protein

Disorders of immunoglobulin (Ig) synthesis that occur in malignant plasma-c ell proliferation may result in either granular (LCDD) or fibrillar (AL) ti ssue deposition of light-chain monoclonal components. The structural featur es that govern the transition from soluble polypeptides to either fibrillar or granular conformational states remain undefined. Among the many factors presumed to play a role in these transitions the net charge of the molecul e has been associated with folding conformation changes. The majority of th e proteins involved in AL amyloidosis show acidic isoelectric points (pI 3. 8-5.2), whereas most L chains with basic pIs deposit in granular patterns. In our studies. 12 kD V kappa III fragment was purified as the main compone nt of the fibrils isolated from myocardium and adipose tissue of the perica rdium obtained post-mortem from an individual with systemic AL amyloidosis. An apparently identical 12 kD VL fragment with the same N-terminal sequenc e constituted the BJ protein present in the urine. This urinary protein exh ibited strikingly cathodic electrophoretic mobility on agarose gels and lac ked retention by anionic exchange chromatography matrices, indicative of a highly basic pi (>10). When it was subjected to in vitro fibril-formation e xperiments, the BJ protein adopted a fibrillar conformation only at acidic pHs, remaining aggregated but not fibrillar at physiological pH. The data i ndicate that a specific tissue deposition pattern involves not only structu ral properties of the protein but rather more complex mechanisms in which a cidic micro-environments may contribute to the stabilization of amyloidogen ic conformations.