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首页> 外文期刊>Journal of Molecular Biology >Limited Proteolysis Reveals That Amyloids from the 3D Domain-Swapping Cystatin B Have a Non-Native beta-Sheet Topology
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Limited Proteolysis Reveals That Amyloids from the 3D Domain-Swapping Cystatin B Have a Non-Native beta-Sheet Topology

机译：有限的蛋白水解揭示了来自3D域交换胱抑素B的淀粉样蛋白具有非天然的β-Sheet拓扑

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3D domain-swapping proteins form multimers by unfolding and then sharing of secondary structure elements, often with native-like interactions. Runaway domain swapping is proposed as a mechanism for folded proteins to form amyloid fibres, with examples including serpins and cystatins. Cystatin C amyloids cause a hereditary form of cerebral amyloid angiopathy whilst cystatin B aggregates are found in cases of Unverricht-Lundborg Syndrome, a progressive form of myoclonic epilepsy. Under conditions that favour fibrillisation, cystatins populate stable 3D domain-swapped dimers both in vitro and in vivo that represent intermediates on route to the formation of fibrils. Previous work on cystatin B amyloid fibrils revealed that the alpha-helical region of the protein becomes disordered and identified the conservation of a continuous 20-residue elongated beta-strand (residues 39-58), the latter being a salient feature of the dimeric 3D domain-swapped structure. Here we apply limited proteolysis to cystatin B amyloid fibrils and show that not only the alpha-helical N-terminal of the protein (residues 1-35) but also the C-terminal of the protein (residues 80-98) can be removed without disturbing the underlying fibril structure. This observation is incompatible with previous models of cystatin amyloid fibrils where the beta-sheet is assumed to retain its native antiparallel arrangement. We conclude that our data favour a more generic, at least partially parallel, arrangement for cystatin beta-sheet structure in mature amyloids and propose a model that remains consistent with available data for amyloids from either cystatin B or cystatin C. (C) 2015 Published by Elsevier Ltd.
机译：3D域交换蛋白通常通过天然结构的相互作用，通过展开然后共享二级结构元件来形成多聚体。失控域交换被提议为折叠蛋白形成淀粉样蛋白纤维的机制，其例子包括丝氨酸蛋白酶抑制剂和半胱氨酸蛋白酶抑制剂。胱抑素C淀粉样蛋白引起遗传性形式的脑淀粉样血管病，而胱抑素B聚集体在Unverricht-Lundborg综合症的病例中发现，这是肌阵挛性癫痫的进展形式。在有利于原纤维化的条件下，半胱氨酸蛋白酶抑制剂在体外和体内均构成稳定的3D结构域交换的二聚体，这些二聚体代表着形成原纤维的中间产物。先前关于胱抑素B淀粉样蛋白原纤维的研究表明，该蛋白质的α-螺旋区域变得混乱，并确定了连续20个残基的延长β链（残基39-58）的保守性，后者是二聚3D的重要特征域交换结构。在这里，我们对半胱氨酸蛋白酶抑制剂B淀粉样蛋白原纤维进行有限的蛋白水解，结果表明，不去除蛋白质的α-螺旋N末端（残基1-35），也可以去除蛋白质的C末端（残基80-98）。干扰潜在的原纤维结构。该观察结果与以前的胱抑素淀粉样蛋白原纤维模型不兼容，在该模型中，β-折叠被认为保留了其天然的反平行排列。我们得出结论，我们的数据支持成熟淀粉样蛋白中半胱氨酸蛋白酶抑制剂β-折叠结构的更通用，至少部分平行的排列，并提出了一个模型，该模型与来自胱抑素B或胱抑素C的淀粉样蛋白的可用数据保持一致。（C）2015由Elsevier Ltd.

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