Chicken NANOG self-associates via a novel folding-upon-binding mechanism
Chicken NANOG self-associates via a novel folding-upon-binding mechanism
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DOI：
10.1096/fj.201700924rr
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发表时间：
2018-05-01
期刊：
影响因子：
4.8
通讯作者：
Han, Jae Yong
中科院分区：
文献类型：
--
作者：
Choi, Hee Jung;Kim, Iktae;Han, Jae Yong
NANOG在高等脊椎动物的多能性获得和谱系规范中起着关键作用，其表达仅限于胚胎发育早期的原始生殖细胞（PGCs）。哺乳动物NANOG通过c端结构域（CTD）中保守的色氨酸重复基序自我结合以维持多能性。然而，鸟类NANOG缺乏保守的基序，其生物学功能的分子机制尚不清楚。在这里，利用光谱和生化方法以及基于细胞的分析，我们报告了鸡NANOG （cNANOG）通过其CTD通过一种新的结合折叠机制进行寡聚。cNANOG的CTD作为单体无序，并在分子间疏水相互作用的驱动下结合成a-螺旋多聚体。CTD中关键芳香残基的突变破坏了这种自结合，导致鸡PGCs和胚皮细胞的增殖丧失。我们的研究结果表明，cNANOG的CTD属于一种新的IDP，它通过自结合转变为螺旋低聚物，使PGCs和胚皮细胞得以维持。
NANOG plays a pivotal role in pluripotency acquisition and lineage specification in higher vertebrates, and its expression is restricted to primordial germ cells (PGCs) during early embryonic development. Mammalian NANOG self-associates via conserved tryptophan-repeat motifs in the C-terminal domain (CTD) to maintain pluripotency. Avian NANOG, however, lacks the conserved motifs, and the molecular mechanism underlying the biologic function is not clearly understood. Here, using spectroscopic and biochemical methods as well as cell-based assays, we report that chicken NANOG (cNANOG) oligomerizes through its CTD via a novel folding-upon-binding mechanism. The CTD of cNANOG is disordered as a monomer and associates into an a-helical multimer driven by intermolecular hydrophobic interactions. Mutation of key aromatic residues in the CTD abrogates the selfassociation, leading to a loss of the proliferation of chicken PGCs and blastoderm cells. Our results demonstrate that the CTD of cNANOG belongs to a novel IDP that switches into a helical oligomer via self-association, enabling the maintenance of PGCs and blastoderm cells.