小热休克蛋白MjHSP16.5对多肽纤维生长的抑制及对成熟纤维的解聚作用

Inhibition of Amyloid Fibrillization and Dissociation of Matured Amyloid Fibrils by Mj HSP16.5

包括老年痴呆症在内的许多疾病与蛋白质或多肽的淀粉样聚集(纤维化)有关.由于这类疾病的机制尚不清楚,因此还没有有效的预防和治疗手段.研究各种因素如小热休克蛋白对蛋白质或多肽淀粉样聚集的影响对开发防治相关疾病的药物具有重要意义.甲状腺素运载蛋白(TTR)及其突变体很容易形成淀粉样纤维,并与多种疾病相关.Mj HSP16.5是一种来源于嗜热古细菌Methanococcus jannaschii的小热休克蛋白,它在酸性条件下具有非常高的分子伴侣活性.本文研究了Mj HSP16.5对WTTR肽(在N端添加了色氨酸的TTR105-115片段,序列为WYTIAALLSPYS)纤维化的影响,发现Mj HSP16.5能够显著地抑制WTTR肽纤维的生长,且在Mj HSP16.5存在下,WTTR肽形成的纤维比正常条件下形成的要显著细小.尤其是Mj HSP16.5还可以使已经成熟的WTTR肽纤维解离.结果表明,Mj HSP16.5抑制多肽纤维的机理可能在于其能够与多肽纤维及纤维种子结合.

The amyloid fibrillization of proteins and peptides is related to many human diseases including Alzheimer＇s disease.Currently there is no effective therapy for these diseases, because the mechanism of the amyloid fibrillization is still not clear.Understanding how to effectively inhibit amyloid formation will shed light on the prevention and treatment of these diseases.Transtheritin （TTR） and its mutants easily form amyloid fibrils and are related to many diseases.Mj HSP16.5, a small heat shock protein （SHSP） from Methanococcus jannaschii shows high chaperone-like activity under acidic conditions, and these conditions promote the fibrillization of many peptides.We studied the influence of Mj HSP16.5 on the fibrillization of the peptide WTTR （sequence：WYTIAALLSPYS, i.e., the 105-115 fragment of TTR with a tryptophan added to its N-terminal）.Mj HSP16.5 was found to significantly inhibit the growth and maturation of the WTTR fibrils resulting in much thinner fibrils compared to those under normal conditions.More interestingly, Mj SHSP16.5 can dissociate the matured WTTR fibrils.Based on our experimental results, a possible inhibition mechanism was proposed in which Mj SHP16.5 interacted with WTTR fibrils and/or seeds.