Cleavage, down-regulation and aggregation of serum amyloid A

Abstract Various diseases cause over-expression of the serum amyloid A protein (SAA), which leads in some, but not all, cases to amyloidosis as a secondary disease. The response to the over-expression involves dissociation of SAA hexamer and subsequent cleavage of the released monomers, most commonly yielding fragments SAA 1−76 of the full-sized SAA 1−104 . We report results from molecular dynamic simulations that probe the role of this cleavage for down-regulating activity and the concentration of SAA. We propose a mechanism that relies on two elements. First, the probability to assemble into hexamers is lower for the fragments than it is for the full-sized protein. Second, unlike other fragments SAA 1−76 can switch between two distinct configurations. The first kind is easy to proteolyze (allowing a fast reduction of SAA concentration) but prone to aggregation, while the situation is opposite for the second kind. If the time scale for amyloid formation is longer than the one for proteolysis, the aggregation-prone species dominates. However, if environmental conditions such as low pH increase the risk of amyloid formation, the ensemble shifts toward the more protected form. We speculate that SAA amyloidosis is a failure of the switching mechanism leading to accumulation of the aggregation-prone species and subsequent amyloid formation.