Heparan sulfate promotes the aggregation of HDL-associated serum amyloid A: evidence for a proamyloidogenic histidine molecular switch
Heparan sulfate promotes the aggregation of HDL-associated serum amyloid A: evidence for a proamyloidogenic histidine molecular switch
复制标题
DOI：
10.1096/fj.09-134981
复制
发表时间：
2009-10-01
期刊：
影响因子：
4.8
通讯作者：
Ancsin, John B.
中科院分区：
文献类型：
--
作者：
Elimova, Elena;Kisilevsky, Robert;Ancsin, John B.
在炎症性疾病期间，血清淀粉样蛋白A（SAA），HDL的急性相载脂蛋白，可以组装成称为AA淀粉样蛋白的组织沉积物。促进淀粉样变性的机制和生理因素在很大程度上是未知的，但可能涉及硫酸乙酰肝素（HS），一种与所有类型的淀粉样蛋白共定位的糖胺聚糖。在这项研究中，我们探讨了HDL-SAA：HS的相互作用，在体外和细胞培养测定，以确定HS结合域，促进天然SAA转化为AA淀粉样蛋白。HS在温和的酸性pH下引起HDL-SAA的重塑，产生富含SAA的聚集体。SAA中负责这种转换的序列基序被鉴定为含有pH敏感性肝素/HS结合位点，作为细胞表面受体的配体发挥作用，并作为SAA聚集的结构焦点。在AA淀粉样蛋白生成的单核细胞培养模型中，对应于该区域的合成肽促进了AA淀粉样蛋白的沉积。该效应是肽序列特异性的，并且依赖于H36的质子化。我们得出结论，SAA与巨噬细胞结合所需的高度保守的基序，在酸性pH条件下，以HS依赖的方式，也可以作为分子开关，指导SAA错误折叠成AA淀粉样蛋白。类似的组氨酸依赖性HS结合位点也在其他淀粉样蛋白生成多肽中发现。Elimova，E.，Kisilevsky河，Ancsin，J. B.硫酸乙酰肝素促进HDL相关血清淀粉样蛋白A的聚集：促淀粉样蛋白生成组氨酸分子开关的证据FASEB J.23，3436-3448（2009）. www.fasebj.org
During inflammatory diseases, serum amyloid A (SAA), an acute-phase apolipoprotein of HDL, can assemble into tissue deposits called AA amyloids. The mechanism and physiological factors promoting amyloidosis are largely unknown but likely involve heparan sulfate (HS), a glycosaminoglycan colocalized with all types of amyloids. In this study, we explored HDL-SAA: HS interactions using in vitro and cell culture assays to identify HS-binding domains that promote the conversion of native SAA into AA amyloid. HS causes the remodeling of HDL-SAA at mildly acidic pH, producing SAA-rich aggregates. A sequence motif in SAA responsible for this conversion was identified that contains a pH-sensitive heparin/HS-binding site, functions as a ligand for a cell surface receptor, and acts as a structural focal point for SAA aggregation. Synthetic peptides corresponding to this region promoted the deposition of AA amyloid in a monocyte culture model for AA amyloidogenesis. The effects were peptide sequence specific and reliant on the protonation of H36. We conclude that a highly conserved motif required for SAA binding to macrophages can, under acidic pH conditions and in an HS-dependent manner, also act as a molecular switch, directing SAA misfolding into AA amyloid. Similar histidine-dependent HS-binding sites are also found in other amyloidogenic polypeptides.-Elimova, E., Kisilevsky, R., Ancsin, J. B. Heparan sulfate promotes the aggregation of HDL-associated serum amyloid A: evidence for a proamyloidogenic histidine molecular switch. FASEB J. 23, 3436-3448 ( 2009). www.fasebj.org