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.
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