中科院，北大连发Cell子刊文章

　　

生物通报道：近期来自中国科学院生物物理研究所，北大生科院的研究人员分别在Cell出版社旗下的Structure杂志，和Current Biology杂志上发表文章，深入系统地研究了细胞极化发生因子Par-3 N-端结构域自组装的分子机理，以及阐述了白虎形成的遗传学机制。

在第一篇文章中，生物大分子国家重点实验室冯巍研究员与孙飞研究员合作，综合了蛋白质晶体学、低温电镜三维重构技术、原子力显微镜以及分子动力学模拟，深入系统地研究了细胞极化发生因子Par-3 N-端结构域自组装的分子机理。研究发现，Par-3 N-端结构域通过静电相互作用形成首尾相接，螺旋上升的组装结构。对相互作用面上的静电相互作用的破坏，使得Par-3失去了调控极性的功能。该项研究成果为综合多种研究手段解析生物大分子复合物的结构提供了一个新的范例。

Par-3在调控各类不同物种的细胞极性方面起到基础性的作用。有研究表明，Par-3在体内可以多聚化。已知Par-3蛋白质包含NTD，PDZ和aPKC结合域等结构域。其中NTD结构域的高聚化对于介导Par-3的聚集起到不可或缺的重要作用。关于Par-3 N-端结构域高聚的分子机理，一直没有得到详尽剖析。冯巍课题组与孙飞课题组合作完成的该项研究成果给该问题画上了句号。

该项研究成果的核心部分Par-3 NTD的螺旋组装体的高分辨率低温电镜三维重构研究工作是由孙飞课题组的张艳助理研究员完成的。这也是我国首次利用低温电镜技术解析的螺旋结构样品的高分辨率结构。

此外，北京大学生命科学学院、北大-清华生命科学联合中心罗述金研究组和生物动态光学成像中心（BIOPIC）、生命科学学院、北大-清华生命科学联合中心李瑞强研究组，与广州长隆野生动物世界等合作单位，揭示了白虎的毛色及相关性状是由毛色决定基因SLC45A2 突变所致。

白虎是虎的亚种孟加拉虎（Panthera tigris tigris）野外发生的一种罕见突变型。与通常的毛色全白和红眼的白化动物不一样，其底色皮毛的颜色呈白色，条纹则呈现深褐色至黑色，而且眼睛呈灰蓝色。尽管野外白虎的记录最早可追溯到16世纪，其遗传机制却一直不为人所知。罗述金研究组利用高通量测序平台，对广州长隆野生动物世界提供的一个由7只白虎和9只黄虎组成的家系进行了全基因组遗传连锁分析，并对其中3只亲本个体进行了全基因组测序，由此确定了白虎由SLC45A2基因的一个氨基酸突变（A477V）所致，这一结果在对另外无亲缘关系的130只虎的基因型分析后得到最终确认。研究组还通过计算结构生物学手段预测了SLC45A2蛋白质三维结构模型，揭示SLC45A2可能是一个具有12个跨膜区的转运蛋白，A477V突变阻碍了转运孔道的畅通，从而影响其功能。

SLC45A2是一个已知的色素决定基因，其多样性与人的肤色以及其他一些动物（马、鸡、小鼠等）的毛色有关。该研究在白虎中发现的SLC45A2基因突变主要影响毛发和皮肤中黄色和红色色素的合成，对黑色色素的影响较弱，不会造成其它器官的功能缺陷。从白虎形成的遗传机理来说，白虎不是白化病个体，它能够很好地适应野外生存，因此，从遗传多样性来说，白虎有一定的保护价值。这一结论结束了长期以来保护生物学界关于白虎是否是一种遗传缺陷的争论，对虎的遗传多样性保护以及白虎的繁殖策略等提供了科学的佐证。

原文摘要：

Structural Insights into the Intrinsic Self-Assembly of Par-3 N-Terminal Domain

Par-3, the central organizer of the Par-3/Par-6/atypical protein kinase C complex, is a multimodular scaffold protein that is essential for cell polarity establishment and maintenance. The N-terminal domain (NTD) of Par-3 is capable of self-association to form filament-like structures, although the underlying mechanism is poorly understood. Here, we determined the crystal structure of Par-3 NTD and solved the filament structure by cryoelectron microscopy. We found that an intrinsic front-to-back interaction mode is important for Par-3 NTD self-association and that both the lateral and longitudinal packing within the filament are mediated by electrostatic interactions. Disruptions of the lateral or longitudinal packing significantly impaired Par-3 NTD self-association and thereby impacted the Par-3-mediated epithelial polarization. We finally demonstrated that a Par-3 NTD-like domain from histidine ammonia-lyase also harbors a similar self-association capacity. This work unequivocally provides the structural basis for Par-3 NTD self-association and characterizes one type of protein domain that can self-assemble via electrostatic interactions.

The genetic basis of white tigers

The white tiger, an elusive Bengal tiger (Panthera tigris tigris) variant with white fur and dark stripes, has fascinated humans for centuries ever since its discovery in the jungles of India [1]. Many white tigers in captivity are inbred in order to maintain this autosomal recessive trait [2,3,4,5] and consequently suffer some health problems, leading to the controversial speculation that the white tiger mutation is perhaps a genetic defect [6]. However, the genetic basis of this phenotype remains unknown. Here, we conducted genome-wide association mapping with restriction-site-associated DNA sequencing (RAD-seq) in a pedigree of 16 captive tigers segregating at the putative white locus, followed by whole-genome sequencing (WGS) of the three parents. Validation in 130 unrelated tigers identified the causative mutation to be an amino acid change (A477V) in the transporter protein SLC45A2. Three-dimensional homology modeling suggests that the substitution may partially block the transporter channel cavity and thus affect melanogenesis. We demonstrate the feasibility of combining RAD-seq and WGS to rapidly map exotic variants in nonmodel organisms. Our results identify the basis of the longstanding white tiger mystery as the same gene underlying color variation in human, horse, and chicken and highlight its significance as part of the species natural polymorphism that is viable in the wild.