We investigate through molecular dynamics simulations why over-expression of the serum amyloid A (SAA), observed in various diseases, leads in some, but not all, cases to amyloidosis as a secondary disease. We propose that SAA amyloidosis is a failure of a mechanism for down-regulating activity and concentration of SAA, which involves dissociation of SAA hexamer and subsequent cleavage of the released monomers, most commonly yielding fragments SAA1-76 of the full-sized protein. This mechanism is based on two elements. First, the fragment is less likely to be assembled into hexamers than that for the full-sized protein. Second, SAA1-76 can switch between two distinct configurations. If the time scale for amyloid formation is longer than the one for proteolysis, the dominant configurations are those that are easy to proteolyze (allowing a fast reduction of SAA concentration) but prone to aggregation. However, if environmental conditions such as low pH increase the danger of amyloid formation, the ensemble shifts toward the second type of configuration, which is less prone to aggregation but also more difficult to proteolyze.

Role of C-terminal cleavage in down-regulating the activity of  serum amyloid A

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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