HEPARAN SULFATE PROMOTES THE REFOLDING AND OLIGOMERIZATION OF SAA1.1: A SHORT SEQUENCE IS IMPLICATED IN THIS MISFOLDING PROCESS

摘要

Heparan sulfate (HS) proteoglycans (perlecan, agrin) co-deposit with amyloid and likely play a prominent role in fibrillogenesis Several groups have identified HS-binding sites on different amyloid-polypeptides (reviewed in 1) including serum amyloid A (SAA) (2) the focus of this study HS and structurally related heparin have also been shown to promote the misfolding and/or fibrillogenesis for Aa, PrP, IAPP, (3-2-microglobulin, SAA, and gelsolin Synthetic polysulfonates, which mimic aspects of HS structure and sugar analogs designed to modify HS biosynthesis can prevent AA-amyloidosis (3,4). Furthermore, a synthetic peptide (27-mer) corresponding to the SAA HS-binding site (1) was found to be a potent inhibitor of AA-fibrillogenesis in a monocytic culture system (5). The experiments described herein provide additional evidence that SAA binds HS and through these interactions becomes misfolded and oligomerized. The physicocheffiical conditions favoring this process were also explored and the peptide sequence of SAA 1.1 driving HS-dependent oligomerization was identified. Our data supports a mechanism for fibrillogenesis in which SAA is transferred from an apolar microenvironment to one more polar where protein unfolding is energetically favored. HS promotion of fibrillogenesis likely involves stabilization of one or more SAA1..1 amyloidogenic intermediates through HS association with residues 17-49 and co-ordinate SAA1.1's rapid assembly into organized pre-fibrillar oligomers.