Buchko Garry W, Abendroth Jan, Robinson Howard, Zhang Yanfeng, Hewitt Stephen N, Edwards Thomas E, Van Voorhis Wesley C, Myler Peter J
Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99352, USA.
J Struct Funct Genomics. 2013 Jun;14(2):47-57. doi: 10.1007/s10969-013-9155-9. Epub 2013 May 25.
Macrophage migration inhibitory factor (MIF) is a eukaryotic cytokine that affects a broad spectrum of immune responses and its activation/inactivation is associated with numerous diseases. During protozoan infections MIF is not only expressed by the host, but, has also been observed to be expressed by some parasites and released into the host. To better understand the biological role of parasitic MIF proteins, the crystal structure of the MIF protein from Giardia lamblia (Gl-MIF), the etiological agent responsible for giardiasis, has been determined at 2.30 Å resolution. The 114-residue protein adopts an α/β fold consisting of a four-stranded β-sheet with two anti-parallel α-helices packed against a face of the β-sheet. An additional short β-strand aligns anti-parallel to β4 of the β-sheet in the adjacent protein unit to help stabilize a trimer, the biologically relevant unit observed in all solved MIF crystal structures to date, and form a discontinuous β-barrel. The structure of Gl-MIF is compared to the MIF structures from humans (Hs-MIF) and three Plasmodium species (falciparum, berghei, and yoelii). The structure of all five MIF proteins are generally similar with the exception of a channel that runs through the center of each trimer complex. Relative to Hs-MIF, there are differences in solvent accessibility and electrostatic potential distribution in the channel of Gl-MIF and the Plasmodium-MIFs due primarily to two "gate-keeper" residues in the parasitic MIFs. For the Plasmodium MIFs the gate-keeper residues are at positions 44 (Y --> R) and 100 (V --> D) and for Gl-MIF it is at position 100 (V --> R). If these gate-keeper residues have a biological function and contribute to the progression of parasitemia they may also form the basis for structure-based drug design targeting parasitic MIF proteins.
巨噬细胞移动抑制因子（MIF）是一种真核细胞因子，可影响广泛的免疫反应，其激活/失活与多种疾病相关。在原生动物感染期间，MIF不仅由宿主表达，而且还观察到一些寄生虫也表达并释放到宿主中。为了更好地理解寄生性MIF蛋白的生物学作用，已确定了导致贾第虫病的病原体——蓝氏贾第鞭毛虫（Gl-MIF）的MIF蛋白的晶体结构，分辨率为2.30 Å。这种114个残基的蛋白质采用α/β折叠结构，由一个四链β-折叠片层和两条反平行的α-螺旋组成，α-螺旋靠在β-折叠片层的一个面上。一条额外的短β-链与相邻蛋白质单元中β-折叠片层的β4反平行排列，以帮助稳定三聚体（这是迄今为止在所有已解析的MIF晶体结构中观察到的生物学相关单元），并形成一个不连续的β-桶。将Gl-MIF的结构与人类（Hs-MIF）和三种疟原虫（恶性疟原虫、伯氏疟原虫和约氏疟原虫）的MIF结构进行了比较。所有五种MIF蛋白的结构总体相似，但每个三聚体复合物中心有一个通道除外。相对于Hs-MIF，Gl-MIF和疟原虫MIF通道中的溶剂可及性和静电势分布存在差异，这主要是由于寄生性MIF中的两个“守门”残基。对于疟原虫MIF，守门残基位于第44位（Y→R）和第100位（V→D），对于Gl-MIF，它位于第100位（V→R）。如果这些守门残基具有生物学功能并有助于寄生虫血症的进展，它们也可能成为针对寄生性MIF蛋白的基于结构的药物设计的基础。
