Cleavage, Downregulation, and Aggregation of Serum Amyloid A.

Wenhua Wang, Prabir Khatua, Ulrich H E Hansmann

The journal of physical chemistry. B 2020 Feb 13

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Various diseases cause overexpression of the serum amyloid A (SAA) protein, which in some cases, but not in all cases, leads to amyloidosis as a secondary disease. Response to the overexpression involves dissociation of the SAA hexamer and subsequent cleavage of the released monomers, most commonly yielding fragments SAA1-76 of the full-sized SAA1-104. We report results from molecular dynamic simulations that probe the role of this cleavage for downregulating the activity and 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, SAA1-76 can switch between two distinct configurations. The first kind is easy to proteolyse (allowing a fast reduction of the SAA concentration) but prone to aggregation, whereas 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 increases the risk of amyloid formation, the ensemble shifts toward the more protected form. We speculate that SAA amyloidosis is a failure of this switching mechanism leading to accumulation of the aggregation-prone species and subsequent amyloid formation.

Citation

Wenhua Wang, Prabir Khatua, Ulrich H E Hansmann. Cleavage, Downregulation, and Aggregation of Serum Amyloid A. The journal of physical chemistry. B. 2020 Feb 13;124(6):1009-1019