An amyloidosis-associated polymorphism does not alter LECT2 stability in vitro

Abstract

AbstractAmyloid fibrils formed from leukocyte chemotactic factor 2 (LECT2), a secreted human cytokine, are associated with kidney failure in the disease amyloid LECT2 (ALECT2) amyloidosis. This rare disease was recognized in 2008 and has a variable prevalence worldwide. The mechanisms which lead to ALECT2 fibril deposition are not known and there are no treatments other than kidney transplant. The LECT2 gene harbors a single nucleotide polymorphism that leads to either a valine or isoleucine residue at position 40 of the mature protein. Most of the individuals diagnosed with ALECT2 amyloidosis are homozygous for valine at this position, which led us to hypothesize that the valine-containing variant of LECT2 protein is less stable and more prone to aggregation than the isoleucine-containing variant. Here, we investigate the structure, stability and aggregation of both variants of recombinant LECT2. Both variants have similar structures in solution; unfold in similar concentrations of urea; and aggregate at similar rates under native-like conditions, forming structures that bind to thioflavin T. Chelation of the structural zinc ion destabilizes both variants to a similar extent, and increases the rate at which they aggregate. We do not observe a consistent difference in stability or aggregation between the variants of LECT2, so we suggest that the presence of the valine residue at position 40 does not determine whether an individual is at increased risk of ALECT2 amyloidosis.