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A structural preview of aquaporin 8 via homology modeling of seven vertebrate isoforms.
BMC Structural Biology Pub Date : 2018-02-17 , DOI: 10.1186/s12900-018-0081-8
Andreas Kirscht 1 , Yonathan Sonntag 1 , Per Kjellbom 1 , Urban Johanson 1
Affiliation  

BACKGROUND Aquaporins (AQPs) facilitate the passage of small neutral polar molecules across membranes of the cell. In animals there are four distinct AQP subfamilies, whereof AQP8 homologues constitute one of the smallest subfamilies with just one member in man. AQP8 conducts water, ammonia, urea, glycerol and H2O2 through various membranes of animal cells. This passive channel has been connected to a number of phenomena, such as volume change of mitochondria, ammonia neurotoxicity, and mitochondrial dysfunction related to oxidative stress. Currently, there is no experimentally determined structure of an AQP8, hence the structural understanding of this subfamily is limited. The recently solved structure of the plant AQP, AtTIP2;1, which has structural and functional features in common with AQP8s, has opened up for construction of homology models that are likely to be more accurate than previous models. RESULTS Here we present homology models of seven vertebrate AQP8s. Modeling based on the AtTIP2;1 structure alone resulted in reasonable models except for the pore being blocked by a phenylalanine that is not present in AtTIP2;1. To achieve an open pore, these models were supplemented with models based on the bacterial water specific AQP, EcAqpZ, creating a chimeric monomeric model for each AQP8 isoform. The selectivity filter (also named the aromatic/arginine region), which defines the permeant substrate profile, comprises five amino acid residues in AtTIP2;1, including a histidine coming from loop C. Compared to AtTIP2;1, the selectivity filters of modelled AQP8s only deviates in that they are slightly more narrow and more hydrophobic due to a phenylalanine replacing the histidine from loop C. Interestingly, the models do not exclude the existence of a side pore beneath loop C similar to that described in the structure of AtTIP2;1. CONCLUSIONS Our models concur that AQP8s are likely to have an AtTIP2;1-like selectivity filter. The detailed description of the expected configuration of residues in the selectivity filters of AQP8s provides an excellent starting point for planning of as well as rationalizing the outcome of mutational studies. Our strategy to compile hybrid models based on several templates may prove useful also for other AQPs for which structural information is limited.

中文翻译:

通过对七个脊椎动物同工型的同源性建模对水通道蛋白8进行结构预览。

背景技术水通道蛋白(AQPs)促进小的中性极性分子穿过细胞膜的通过。在动物中,有四个不同的AQP亚家族,其中AQP8同源物是最小的亚家族之一,在人类中只有一个成员。AQP8通过动物细胞的各种膜传导水,氨,尿素,甘油和H2O2。该被动通道与许多现象有关,例如线粒体的体积变化,氨神经毒性和与氧化应激有关的线粒体功能障碍。当前,没有实验确定的AQP8结构,因此对该亚家族的结构理解受到限制。工厂AQP最近解决的结构AtTIP2; 1具有与AQP8相同的结构和功能特征,已为构建可能比以前的模型更精确的同源性模型开辟了道路。结果在这里我们提出了七个脊椎动物AQP8s的同源性模型。单独基于AtTIP2; 1结构进行建模可得出合理的模型,但孔隙会被AtTIP2; 1中不存在的苯丙氨酸阻塞。为了实现开孔,这些模型补充了基于细菌水特异性AQP,EcAqpZ的模型,从而为每个AQP8亚型创建了一个嵌合单体模型。定义渗透底物分布的选择性过滤器(也称为芳香族/精氨酸区域),在AtTIP2; 1中包含5个氨基酸残基,包括来自环C的组氨酸。与AtTIP2; 1相比,建模的AQP8s的选择性过滤器的不同之处仅在于,由于苯丙氨酸替代了环C中的组氨酸,它们略微更窄且更具疏水性。有趣的是,该模型并未排除环C下的侧孔的存在,类似于AtTIP2的结构; 1。结论我们的模型认为AQP8可能具有一个AtTIP2; 1-like选择性过滤器。AQP8s选择性过滤器中残基的预期构型的详细说明为突变研究的计划和合理化提供了极好的起点。我们基于几个模板编译混合模型的策略可能也对其他结构信息有限的AQP有用。模型不排除类似于AtTIP2结构中所描述的那样,在回路C下存在侧孔; 1。结论我们的模型认为AQP8可能具有一个AtTIP2; 1-like选择性过滤器。AQP8s选择性过滤器中残基的预期构型的详细说明为突变研究的计划和合理化提供了一个极好的起点。我们基于几个模板编译混合模型的策略可能也对其他结构信息有限的AQP有用。模型不排除类似于AtTIP2结构中所描述的那样,在回路C下存在侧孔; 1。结论我们的模型认为AQP8可能具有一个AtTIP2; 1-like选择性过滤器。AQP8s选择性过滤器中残基的预期构型的详细说明为突变研究的计划和合理化提供了极好的起点。我们基于几个模板编译混合模型的策略可能也对结构信息有限的其他AQP有用。AQP8s选择性过滤器中残基的预期构型的详细说明为突变研究的计划和合理化提供了极好的起点。我们基于几个模板编译混合模型的策略可能也对其他结构信息有限的AQP有用。AQP8s选择性过滤器中残基的预期构型的详细说明为突变研究的计划和合理化提供了极好的起点。我们基于几个模板编译混合模型的策略可能也对其他结构信息有限的AQP有用。
更新日期:2018-02-17
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