Mutations in the gelsolin protein are responsible for a rare conformational disease known as AGel amyloidosis. Four of these mutations are hosted by the second domain of the protein (G2): D187N/Y, G167R and N184K. The impact of the latter has been so far evaluated only by studies on the isolated G2. Here we report the characterization of full-length gelsolin carrying the N184K mutation and compare the findings with those obtained on the wild type and the other variants. The crystallographic structure of the N184K variant in the Ca2+-free conformation shows remarkable similarities with the wild type protein. Only minimal local rearrangements can be observed and the mutant is as efficient as the wild type in severing filamentous actin. However, the thermal stability of the pathological variant is compromised in the Ca2+-free conditions. These data suggest that the N to K substitution causes a local disruption of the H-bond network in the core of the G2 domain. Such a subtle rearrangement of the connections does not lead to significant conformational changes but severely affects the stability of the protein.

中文翻译：

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凝溶胶蛋白的 N184K 淀粉样变体的结构突出了 H 键网络对蛋白质稳定性和聚集特性的作用。

凝溶胶蛋白中的突变导致了一种称为 Agel 淀粉样变性的罕见构象疾病。其中四个突变由蛋白质的第二个域 (G2) 承载：D187N/Y、G167R 和 N184K。迄今为止，仅通过对孤立 G2 的研究评估了后者的影响。在这里，我们报告了携带 N184K 突变的全长凝溶胶蛋白的特征，并将这些发现与野生型和其他变体的发现进行了比较。无 Ca2+ 构象的 N184K 变体的晶体结构显示出与野生型蛋白质的显着相似性。只能观察到最小的局部重排，并且突变体在切断丝状肌动蛋白方面与野生型一样有效。然而，病理变体的热稳定性在无 Ca2+ 条件下受到损害。这些数据表明 N 到 K 的替换导致 G2 域核心中 H 键网络的局部中断。这种微妙的连接重排不会导致显着的构象变化，但会严重影响蛋白质的稳定性。