Chiti F, Taddei N, Stefani M, Dobson C M, Ramponi G
Dipartimento di Scienze Biochimiche, Universitá degli Studi di Firenze, 50134 Firenze, Italy.
Protein Sci. 2001 Apr;10(4):879-86. doi: 10.1110/ps.42401.
It is known that human muscle acylphosphatase (AcP) is able, under appropriate conditions in vitro, to aggregate and form amyloid fibrils of the type associated with human diseases. A number of compounds were tested for their ability to bind specifically to the native conformation of AcP under conditions favoring denaturation and subsequent aggregation and fibril formation. Compounds displaying different binding affinities for AcP were selected and their ability to inhibit protein fibrillization in vitro was evaluated. We found that compounds displaying a relatively high affinity for AcP are able to significantly delay protein fibrillization, mimicking the effect of stabilizing mutations; in addition, the effectiveness of such outcome correlates positively to both ligand concentration and affinity to the native state of AcP. By contrast, the inhibitory effect of ligands on AcP aggregation disappears in a mutant protein in which such binding affinity is lost. These results indicate that the stabilization of the native conformation of amyloidogenic proteins by specific ligand binding can be a strategy of general interest to inhibit amyloid formation in vivo.
已知人肌肉酰基磷酸酶（AcP）在体外适当条件下能够聚集并形成与人类疾病相关的淀粉样纤维。在有利于变性以及随后聚集和纤维形成的条件下，测试了多种化合物与AcP天然构象特异性结合的能力。选择了对AcP表现出不同结合亲和力的化合物，并评估了它们在体外抑制蛋白质纤维化的能力。我们发现，对AcP表现出相对较高亲和力的化合物能够显著延迟蛋白质纤维化，模拟稳定突变的效果；此外，这种结果的有效性与配体浓度以及对AcP天然状态的亲和力均呈正相关。相比之下，在失去这种结合亲和力的突变蛋白中，配体对AcP聚集的抑制作用消失。这些结果表明，通过特异性配体结合来稳定淀粉样蛋白原性蛋白质的天然构象可能是一种在体内抑制淀粉样蛋白形成的普遍关注策略。
