Information Génomique et Structurale (CNRS UPR2589), Aix-Marseille Université, Mediterranean Institute of Microbiology, Parc Scientifique de Luminy, Marseille, France.
PLoS One. 2011 Apr 11;6(4):e18528. doi: 10.1371/journal.pone.0018528.
Nosocomial diseases due to Candida albicans infections are in constant rise in hospitals, where they cause serious complications to already fragile intensive care patients. Antifungal drug resistance is fast becoming a serious issue due to the emergence of strains resistant to currently available antifungal agents. Thus the urgency to identify new potential protein targets, the function and structure of which may guide the development of new antifungal drugs. In this context, we initiated a comparative genomics study in search of promising protein coding genes among the most conserved ones in reference fungal genomes. The CA3427 gene was selected on the basis of its presence among pathogenic fungi contrasting with its absence in the non pathogenic Saccharomyces cerevisiae. We report the crystal 3D-structure of the Candida albicans CA3427 protein at 2.1 Å resolution. The combined analysis of its sequence and structure reveals a structural fold originally associated with periplasmic binding proteins. The CA3427 structure highlights a binding site located between the two protein domains, corresponding to a sequence segment conserved among fungi. Two crystal forms of CA3427 were found, suggesting that the presence or absence of a ligand at the proposed binding site might trigger a "Venus flytrap" motion, coupled to the previously described activity of bacterial periplasmic binding proteins. The conserved binding site defines a new subfamily of periplasmic binding proteins also found in many bacteria of the bacteroidetes division, in a choanoflagellate (a free-living unicellular and colonial flagellate eukaryote) and in a placozoan (the closest multicellular relative of animals). A phylogenetic analysis suggests that this gene family originated in bacteria before its horizontal transfer to an ancestral eukaryote prior to the radiation of fungi. It was then lost by the Saccharomycetales which include Saccharomyces cerevisiae.
医院中由于白色念珠菌感染导致的院内疾病不断增加，这些疾病会给已经脆弱的重症监护患者带来严重的并发症。由于现有抗真菌药物的耐药菌株的出现，抗真菌药物耐药性迅速成为一个严重的问题。因此，迫切需要确定新的潜在蛋白质靶标，这些靶标的功能和结构可能指导新的抗真菌药物的开发。在这种情况下，我们启动了一项比较基因组学研究，旨在从参考真菌基因组中最保守的蛋白质编码基因中寻找有前途的基因。CA3427 基因是基于其在致病真菌中的存在而被选中的，而在非致病性酿酒酵母中则不存在。我们报告了白色念珠菌 CA3427 蛋白的晶体 3D 结构，分辨率为 2.1 Å。对其序列和结构的综合分析揭示了一种与周质结合蛋白最初相关的结构折叠。CA3427 结构突出了一个位于两个蛋白质结构域之间的结合位点，该位点对应于真菌中保守的序列片段。发现了 CA3427 的两种晶体形式，这表明配体在提议的结合位点的存在或不存在可能会触发“捕蝇草”运动，与先前描述的细菌周质结合蛋白的活性相关。保守的结合位点定义了一个新的周质结合蛋白亚家族，也存在于许多拟杆菌门细菌、领鞭毛虫（一种自由生活的单细胞和群体鞭毛虫真核生物）和盘基网柄菌（与动物最接近的多细胞相关生物）中。系统发育分析表明，该基因家族起源于细菌，然后在真菌辐射之前水平转移到一个祖先真核生物中。随后，它在包括酿酒酵母在内的 Saccharomycetales 中丢失了。
