Premium
Structural and kinetic differences in oligomerization‐fibrillation of serum amyloid A and not the intrinsic amyloidogenicity may contribute to pathogenesis in AA amyloidosis
Author(s) -
Srinivasan Saipraveen,
Patke Sanket,
Aguilera Javier J,
Kane Ravi S,
Colon Wilfredo
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.996.11
Subject(s) - amyloidosis , chemistry , pathogenesis , aa amyloidosis , fibril , gene isoform , amyloid (mycology) , amyloid fibril , kinetics , serum amyloid a , biophysics , biochemistry , biology , medicine , amyloid β , gene , immunology , pathology , inflammation , disease , inorganic chemistry , familial mediterranean fever , physics , quantum mechanics
Acute‐phase protein serum amyloid A (SAA), specifically the isoform SAA1.1, is implicated in murine reactive AA amyloidosis. However, the mechanism of pathogenesis remains elusive to date. The co‐expressed SAA2.1 and the hybrid SAA2.2, found exclusively in CE/J type mouse, are non‐pathogenic. The proteins show remarkable differences in oligomeric propensities, fibrillation kinetics and thermal stabilities in vitro in spite of high degree of sequence homology. Using Thioflavin T fluorescence and atomic force microscopy (AFM), we show that at 37 °C, SAA1.1 aggregates as spherical oligomers and requires several days to form protofibrils and fibrils. SAA2.1 and SAA2.2 rapidly aggregates to form protofibrils leading to fibrillation (Fig. 1). Spherical oligomers showed lipid bilayer permeabilization, not exhibited by protofibrils or fibrils. Mutations relating SAA1.1 and hybrid SAA2.2 show the important role of each of the differing residues on the overall stability, assembly kinetics and aggregation pathway of the two isoforms. These factors will likely play an important role in the diverse pathogenicity among SAA isoforms across species, opening new venues towards understanding the molecular basis of AA amyloidosis and developing novel therapeutics. This work was supported by a Grant from the NIH (R01 AG028158) to W.C.