Book of Abstracts: Albany 2011
June 14-18 2011
©Adenine Press (2010)
Understanding The Molecular Basis Of Pathogenicity or Lack Thereof Of Serum Amyloid A Isoforms
Acute-phase protein Serum Amyloid A (SAA) is an important biomarker of inflammation and the precursor protein responsible for amyloid A (AA) amyloidosis. Under normal circumstance, SAA is found associated with high-density lipoproteins (HDL), but during infection or injury, SAA levels can increase as high as 1000-fold in ~24hrs. Under chronic inflammatory conditions, persistence of high levels of SAA leads to amyloid deposits composing of whole length and fragments of SAA leading to the systemic AA amyloidosis disease. In mouse models, SAA1.1 predominates in amyloid deposits both as full length and fragmented forms. However, the CE/J type mouse, which expresses a single isoform (i.e. SAA2.2), was resistant to amyloidosis. SAA1.1 and SAA2.2 differ only by six amino acids, suggesting that factors such as fibrillation kinetics, oligomeric states and ligand interactions might play a critical role in determining their pathogenicity. The present study attempts to understand the oligomeric and aggregation mechanism of the pathological and non-pathological forms of SAA, SAA1.1 and SAA2.2 respectively. Our data show that both SAA isoforms exhibit marked differences in oligomeric propensities, fibrillation kinetics and thermal stabilities suggesting the importance of location of specific amino acid residues. SAA1.1 was found to be more intrinsically disordered and exhibited low thermal stability when compared to SAA2.2. Furthermore, SAA1.1 showed a longer lag phase (3-4days) prior to fibrillation, when compared to SAA2.2 (3-6hrs). To obtain insights on the molecular basis of these observed differences, point mutations were performed on SAA2.2 to make it resemble SAA1.1, one amino acid at a time. Overall, comparison of the stability, oligomeric structure and aggregation properties of SAA2.2 and SAA1.1 provides insight that explains their difference in pathogenicity. Furthermore, the intrinsically disordered structure of SAA2.2 and SAA1.1 and their ability to form a diversity of self-assembled structures at 37°C suggests that the structure of SAA might be modulated in vivo to form different biologically relevant species.
Sai Praveen Srinivasan 1, 2
1Department of Chemistry and Chemical Biology