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

Abstract

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.

Identification of Oleanolic Acid as Allosteric Agonist of Integrin αM by Combination of In Silico Modeling and In Vitro Analysis

“…The analysis of the dynamic behavior of key regions identified by RMSF analysis (regions with higher RMSF) in different systems was performed by PyEMMA (Scherer et al, 2015) as previous described (Jin et al, 2019). Briefly, the coordinations of Cα atoms in each region were used to define the initial model, and dimension of input coordinates was reduced by TICA (Time-Lagged Independent Component Analysis) on two dimensions.…”

MFGE8, ALB, APOB, APOE, SAA1, A2M, and C3 as Novel Biomarkers for Stress Cardiomyopathy

“…SAA promotes chemotaxis of monocytes and neutrophils and plays a key role in various functions such as lipoprotein metabolism, cholesterol transport, and host defense [19]. Previous studies have shown that SAA1 plasma levels have increased dramatically in response to tissue damage, infection, and various emergencies [20,21]. So SAA1 is also involved in the pathogenesis of SCM, and its mechanism is similar to that of C3.…”

Atomic-Resolution Experimental Structural Biology and Molecular Dynamics Simulations of Hyaluronan and Its Complexes

“…MM-GBSA analysis of molecular dynamics trajectories seeded with various docked conformations of glycosaminoglycans showed that hyaluronan could simultaneously bridge both proteins in the MMP2/TIMP3 complex and stabilize the complex to increase MMP2 activity, unlike other glycosaminoglycans [ 178 ]. Two different forms of serum amyloid A protein, only one of which is found in amyloid deposits, were independently simulated with hyaluronan, and these microsecond-scale trajectories showed distinct hyaluronan binding patterns that may be important to the initial protein oligomerization leading to amyloid formation [ 179 ]. The polysaccharide lyase from the Stenotrophomonas maltophilia bacterium has pH-dependent activity against three chemically dissimilar carbohydrates, including hyaluronan, and simulation data directly correlated stability of hyaluronan–protein binding at various pH values with hyaluronan lyase activity of the enzyme as a function of pH [ 180 ].…”