Comparative Study on Hyaluronic Acid Binding to Murine SAA1.1 and SAA2.2.

Persistently high plasma levels of serum amyloid A (SAA) may induce AA amyloidosis in various organs causing their dysfunction. Although SAA isoforms share a high degree of homology, only the SAA1.1 isoform is found in amyloid deposits. SAA1.1 misfolding is a nucleation-dependent process with dimer and trimer formation playing a major role in SAA fibril formation through self-catalyzed recruitment of native SAA molecules. Yet, a structural model of initial SAA oligomerization is still missing. In this study, we constructed a loosely associated model for murine SAA1.1 and SAA2.2 dimers in the presence or absence of hyaluronic acid as an exemplary glycosaminoglycan, a factor known to facilitate SAA fibril formation. Molecular dynamics simulations predicted that hyaluronic acid finally stabilized in a different binding pocket of the pathogenic SAA1.1 dimer compared to the nonpathogenic SAA2.2 dimer. Besides, Markov state modeling points to dynamic behavioral differences between the linker region of SAA1.1 and SAA2.2 and identifies a state unique to pathogenic SAA1.1 while bound to hyaluronic acid. The presence or absence of hyaluronic acid, as well as the dimer interface switch, affects dynamic behavior and possible oligomeric states, proposing a conceivable clue to the deviant pathogenicity of the two SAA isoforms.