title: Pathogenic serum amyloid A 1.1 shows a long oligomer-rich fibrillation lag phase contrary to the highly amyloidogenic non-pathogenic SAA2.2.
abstract: Serum amyloid A (SAA) is best known for being the main component of amyloid in the inflammation-related disease amyloid A (AA) amyloidosis. Despite the high sequence identity among different SAA isoforms, not all SAA proteins are pathogenic. In most mouse strains, the AA deposits mostly consist of SAA1.1. Conversely, the CE/J type mouse expresses a single non-pathogenic SAA2.2 protein that is 94% identical to SAA1.1. Here we show that SAA1.1 and SAA2.2 differ in their quaternary structure, fibrillation kinetics, prefibrillar oligomers, and fibril morphology. At 37 °C and inflammation-related SAA concentrations, SAA1.1 exhibits an oligomer-rich fibrillation lag phase of a few days, whereas SAA2.2 shows virtually no lag phase and forms small fibrils within a few hours. Deep UV resonance Raman, far UV-circular dichroism, atomic force microscopy, and fibrillation cross-seeding experiments suggest that SAA1.1 and SAA2.2 fibrils possess different morphology. Both the long-lived oligomers of pathogenic SAA1.1 and the fleeting prefibrillar oligomers of non-pathogenic SAA2.2, but not their respective amyloid fibrils, permeabilized synthetic bilayer membranes in vitro. This study represents the first comprehensive comparison between the biophysical properties of SAA isoforms with distinct pathogenicities, and the results suggest that structural and kinetic differences in the oligomerization-fibrillation of SAA1.1 and SAA2.2, more than their intrinsic amyloidogenicity, may contribute to their diverse pathogenicity.
authors.affiliation: Department of Chemistry and Chemical Biology, Rensselaer Polytechnic Institute, Troy, New York 12180, USA.
authors.forename: Saipraveen
authors.initials: S
authors.lastname: Srinivasan
authors.forename: Sanket
authors.initials: S
authors.lastname: Patke
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.forename: Zhuqiu
authors.initials: Z
authors.lastname: Ye
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Litt
authors.forename: Sunit K
authors.initials: SK
authors.lastname: Srivastava
authors.forename: Maria M
authors.initials: MM
authors.lastname: Lopez
authors.forename: Dmitry
authors.initials: D
authors.lastname: Kurouski
authors.forename: Igor K
authors.initials: IK
authors.lastname: Lednev
authors.forename: Ravi S
authors.initials: RS
authors.lastname: Kane
authors.forename: Wilfredo
authors.initials: W
authors.lastname: Colón
mesh_terms: D000686:Amyloidosis / Q000378:metabolism*; D000818:Animals; D001703:Biophysics / Q000379:methods; D002942:Circular Dichroism; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation; D007700:Kinetics; D051379:Mice; D018625:Microscopy, Atomic Force / Q000379:methods; D011485:Protein Binding; D011489:Protein Denaturation; D017510:Protein Folding; D020033:Protein Isoforms; D011994:Recombinant Proteins / Q000737:chemistry; D000685:Serum Amyloid A Protein / Q000737:chemistry* / Q000378:metabolism; D013056:Spectrophotometry, Ultraviolet / Q000379:methods
chemical_list: D020033:Protein Isoforms; D011994:Recombinant Proteins; C083772:SAA2 protein, human; C489995:Saa2 protein, mouse; D000685:Serum Amyloid A Protein