Focus on molecules: Pax-6, the eye master.
Focus on molecules: Pax-6, the eye master.
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DOI：
10.1016/j.exer.2005.11.019
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发表时间：
2006-08
影响因子：
3.4
通讯作者：
P. Tsonis;E. Fuentes
中科院分区：
文献类型：
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作者：
P. Tsonis;E. Fuentes
Pax-6属于配对盒基因家族，其包含标志性配对盒结构域（PD）和同源盒结构域（HD），随后是富含脯氨酸丝氨酸的结构域（PST）（图1A）。Pax-6蛋白含有422个氨基酸和至少一种转录物变体Pax-6-5a，其在PD中含有14个氨基酸的插入物（在氨基酸位置47处）。PD使用N-末端和C-末端亚结构域以二分方式结合DNA。5a插入物通过N-末端亚结构域消除DNA结合，表明C-末端亚结构域决定该变体中的靶特异性。已经确定了与26-bp最佳DNA双链体复合的配对盒结构域的结构（Xu等人，1999）（图1B）。该结构提供了Pax-6 PD和DNA之间相互作用的详细模型，特别是N-、C-末端亚结构域和接头区如何结合联合收割机以实现DNA结合特异性。具体地，N-和C-末端亚结构域都折叠成螺旋-转角螺旋基序，使人想起同源盒结构域折叠（Xu et al.，1999年）。DNA相互作用的主要位点是通过所谓的“识别”螺旋a3和a6（图1B）。事实上，a3中的残基47（以及较小程度的残基42和44）决定了Pax家族内的DNA特异性。有趣的是，N-和C-末端结构域之间的接头也参与DNA识别和特异性。最后，该结构还提供了一个框架，用于理解已知与疾病有关的突变的影响（图1C，见下文）。
Pax-6 belongs to the family of paired box genes that contain both the hallmark paired box domain (PD) and a homeo box domain (HD), followed by a prolineeserineethreonine rich domain (PST)(Fig. 1A). The Pax-6 protein contains 422 aa and at least one transcript variant, Pax-6-5a that contains a 14 aa insert in the PD (at amino acid position 47). The PD binds DNA in a bipartite fashion using the N-terminal and C-terminal subdomains. The 5a insert abrogates DNA binding by the N-terminal subdomain suggesting that the C-terminal subdomain dictates target specificity in this variant. The structure of the paired box domain in complex with a 26-bp optimal DNA duplex has been determined (Xu et al., 1999)(Fig. 1B). This structure provides a detailed model of the interactions between Pax-6 PD and DNA, and in particular how the N-, C-terminal subdomains and linker region combine to achieve DNA binding specificity. Specifically, both the N-and C-terminal subdomains fold into a helix-turnhelix motif, reminiscent of the homeo box domain fold (Xu et al., 1999). The primary sites of DNA interaction occur by the so-called ‘‘recognition’’helices a3 anda6 (Fig. 1B). Indeed, residue 47 in a3 (and residues 42 and 44 to a lesser degree) dictates DNA specificity within the Pax family. Interestingly, the linker between the N-and C-terminal domains is also involved in DNA recognition and specificity. Finally, the structure also provides a framework for understanding the effect of mutations known to be involved in disease (Fig. 1C, see below).