Serum amyloid A (SAA) belongs to a highly conserved family of small proteins that appear to play a central role in cholesterol metabolism and the inflammatory response. SAA is mainly synthesized by the liver and secreted to the plasma where it binds to high density lipoprotein (HDL), but it is also expressed in normal and diseased tissue, including atherosclerotic plaques and the brains of patients with Alzheimer's disease. During chronic inflammation the concentration of SAA can increase up to 1000 fold, and sometimes form amyloid fibril deposits in major organs, leading to the usually fatal disease of amyloid A (AA) amyloidosis. There is no cure for AA amyloidosis, which is currently one of the most common systemic amyloid diseases worldwide. In mouse, AA amyloidosis can be induced by causing an inflammatory response. Nevertheless, a particular mouse strain (CE/J) contains a single isoform of SAA (SAA2.2) that is resistant to amyloid deposition in vivo during chronic inflammation, despite being 94% identical to the amyloidogenic SAA1.1 isoform. The goal of the proposed research is to study the amyloid formation mechanism of the mouse isoform SAA2.2 and the highly amyloidogenic mouse isoform SAA1.1 to understand the structural, biochemical, and biophysical basis for their different propensities for amyloid formation. Using various, analytical, biophysical, and biochemical methods, the aims of this application are to investigate (Aim 1) the mechanism of SAA2.2 and SAA1.1 amyloid formation, (Aim 2) the role of zinc, calcium, and HDL on the structure, stability and amyloid formation of SAA2.2 and SAA1.1, and (Aim 3) the structural basis for the high in vivo amyloidogenicity of SAA1.1. The long-term goal is to understand the structure, ligand-binding properties, and the molecular basis for the amyloidogenicity of SAA to allow the design of effective preventive or therapeutic approaches against AA amyloidosis. Considering the wide expression profile of SAA in normal and diseased tissue, and its large number of putative functions, it appears that SAA may not just be a marker for inflammation, but rather, may play an active role in the process of many inflammation- related diseases. Therefore, a better understanding of the biochemical and biophysical properties of SAA, as will result from the proposed studies, may shed some light towards understanding how it participates in the process of inflammation.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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Biophysics of Neural Systems Study Section (BPNS)
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Velazquez, Jose M
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Rensselaer Polytechnic Institute
Schools of Arts and Sciences
United States
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Colón, Wilfredo; Aguilera, J Javier; Srinivasan, Saipraveen (2015) Intrinsic Stability, Oligomerization, and Amyloidogenicity of HDL-Free Serum Amyloid A. Adv Exp Med Biol 855:117-34
Aguilera, J Javier; Zhang, Fuming; Beaudet, Julie M et al. (2014) Divergent effect of glycosaminoglycans on the in vitro aggregation of serum amyloid A. Biochimie 104:70-80
Patke, Sanket; Srinivasan, Saipraveen; Maheshwari, Ronak et al. (2013) Characterization of the oligomerization and aggregation of human Serum Amyloid A. PLoS One 8:e64974
Srinivasan, Saipraveen; Patke, Sanket; Wang, Yun et al. (2013) Pathogenic serum amyloid A 1.1 shows a long oligomer-rich fibrillation lag phase contrary to the highly amyloidogenic non-pathogenic SAA2.2. J Biol Chem 288:2744-55
Patke, Sanket; Maheshwari, Ronak; Litt, Jeffrey et al. (2012) Influence of the carboxy terminus of serum amyloid A on protein oligomerization, misfolding, and fibril formation. Biochemistry 51:3092-9
Ye, Zhuqiu; Bayron Poueymiroy, Diane; Aguilera, J Javier et al. (2011) Inflammation protein SAA2.2 spontaneously forms marginally stable amyloid fibrils at physiological temperature. Biochemistry 50:9184-91
Wang, Yun; Srinivasan, Saipraveen; Ye, Zhuqiu et al. (2011) Serum amyloid A 2.2 refolds into a octameric oligomer that slowly converts to a more stable hexamer. Biochem Biophys Res Commun 407:725-9