title: Inflammation protein SAA2.2 spontaneously forms marginally stable amyloid fibrils at physiological temperature.
abstract: For nearly four decades, the formation of amyloid fibrils by the inflammation-related protein serum amyloid A (SAA) has been pathologically linked to the disease amyloid A (AA) amyloidosis. However, here we show that the nonpathogenic murine SAA2.2 spontaneously forms marginally stable amyloid fibrils at 37 °C that exhibit cross-beta structure, binding to thioflavin T, and fibrillation by a nucleation-dependent seeding mechanism. In contrast to the high stability of most known amyloid fibrils to thermal and chemical denaturation, experiments monitored by glutaraldehyde cross-linking/SDS-PAGE, thioflavin T fluorescence, and light scattering (OD(600)) showed that the mature amyloid fibrils of SAA2.2 dissociate upon incubation in >1.0 M urea or >45 °C. When considering the nonpathogenic nature of SAA2.2 and its ~1000-fold increased concentration in plasma during an inflammatory response, its extreme in vitro amyloidogenicity under physiological-like conditions suggest that SAA amyloid might play a functional role during inflammation. Of general significance, the combination of methods used here is convenient for exploring the stability of amyloid fibrils that are sensitive to urea and temperature. Furthermore, our studies imply that analogous to globular proteins, which can possess structures ranging from intrinsically disordered to extremely stable, amyloid fibrils formed in vivo might have a broader range of stabilities than previously appreciated with profound functional and pathological implications.
authors.affiliation: Department of Chemistry and Chemical Biology, and Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York 12180, United States.
authors.forename: Zhuqiu
authors.initials: Z
authors.lastname: Ye
authors.forename: Diane
authors.initials: D
authors.lastname: Bayron Poueymiroy
authors.forename: J Javier
authors.initials: JJ
authors.lastname: Aguilera
authors.forename: Saipraveen
authors.initials: S
authors.lastname: Srinivasan
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.forename: Louise C
authors.initials: LC
authors.lastname: Serpell
authors.forename: Wilfredo
authors.initials: W
authors.lastname: Colón
mesh_terms: D000682:Amyloid / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D000686:Amyloidosis / Q000378:metabolism; D000818:Animals; D052160:Benzothiazoles; D004591:Electrophoresis, Polyacrylamide Gel; D051379:Mice; D011485:Protein Binding; D055550:Protein Stability; D017433:Protein Structure, Secondary; D000685:Serum Amyloid A Protein / Q000737:chemistry / Q000378:metabolism*; D013696:Temperature; D013844:Thiazoles / Q000378:metabolism
chemical_list: D000682:Amyloid; D052160:Benzothiazoles; C489995:Saa2 protein, mouse; D000685:Serum Amyloid A Protein; D013844:Thiazoles; C009462:thioflavin T