Departament de Bioquímica i Biologia Molecular, Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, Spain.
Antioxid Redox Signal. 2012 Jan 1;16(1):1-15. doi: 10.1089/ars.2011.3936. Epub 2011 Sep 15.
The failure of proteins to fold or to remain folded very often leads to their deposition into amyloid fibrils and is the origin of a variety of human diseases. Accordingly, mutations that destabilize the native conformation are associated with pathological phenotypes in several protein models. Protein backbone cyclization by disulfide bond crosslinking strongly reduces the entropy of the unfolded state and, usually, increases protein stability. The effect of protein cyclization on the thermodynamic and kinetics of folding has been extensively studied, but little is know on its effect on aggregation reactions.
The SRC homology 3 domain (SH3) of p85α subunit of bovine phosphatidyl-inositol-3'-kinase (PI3-SH3) domain is a small globular protein, whose folding and amyloid properties are well characterized. Here we describe the effect of polypeptide backbone cyclization on both processes.
We show that a cyclized PI3-SH3 variant is more stable, folds faster, aggregates slower, and forms conformationally and functionally different amyloid fibrils than the wild-type domain.
Disulfide bridges may act as key molecular determinants of both productive protein folding and deleterious aggregation reactions.
蛋白质折叠或保持折叠的失败常常导致其沉积为淀粉样纤维，这是多种人类疾病的起源。因此，使天然构象不稳定的突变与几种蛋白质模型中的病理表型相关。通过二硫键交联使蛋白质主链环化强烈降低了无规卷曲状态的熵，通常会增加蛋白质稳定性。蛋白质环化对折叠热力学和动力学的影响已得到广泛研究，但对其对聚集反应的影响知之甚少。
牛磷脂酰肌醇-3'-激酶（PI3）SH3 结构域 p85α 亚基的Src 同源结构域 3（SH3）是一种小的球形蛋白质，其折叠和淀粉样性质得到了很好的描述。在这里，我们描述了多肽主链环化对这两个过程的影响。
我们发现，与野生型结构域相比，环化的 PI3-SH3 变体更稳定、折叠更快、聚集更慢，并且形成结构和功能不同的淀粉样纤维。
二硫键可能是蛋白质折叠和有害聚集反应的关键分子决定因素。
