3 years ago

Structural and mechanistic insights into nuclear transport and delivery of the critical pluripotency factor Oct4 to DNA

Structural and mechanistic insights into nuclear transport and delivery of the critical pluripotency factor Oct4 to DNA
Yayoi Maruoka, Takahide Okuyama, Masaaki Ikeda, Ryosuke Yamagishi, Jiro Shimada, Hiroki Kaneko

Oct4 is a master regulator of the induction and maintenance of cellular pluripotency, and has crucial roles in early stages of differentiation. It is the only factor that cannot be substituted by other members of the same protein family to induce pluripotency. However, although Oct4 nuclear transport and delivery to target DNA are critical events for reprogramming to pluripotency, little is known about the molecular mechanism. Oct4 is imported to the nucleus by the classical nuclear transport mechanism, which requires importin α as an adaptor to bind the nuclear localization signal (NLS). Although there are structures of complexes of the NLS of transcription factors (TFs) in complex with importin α, there are no structures available for complexes involving intact TFs. We have therefore modeled the structure of the complex of the whole Oct4 POU domain and importin α2 using protein-protein docking and molecular dynamics. The model explains how the Ebola virus VP24 protein has a negative effect on the nuclear import of STAT1 by importin α but not on Oct4, and how Nup 50 facilitates cargo release from importin α. The model demonstrates the structural differences between the Oct4 importin α bound and DNA bound crystal states. We propose that the ‘expanded linker’ between the two DNA-binding domains of Oct4 is an intrinsically disordered region and that its conformational changes have a key role in the recognition/binding to both DNA and importin α. Moreover, we propose that this structural change enables efficient delivery to DNA after release from importin α.

Publisher URL: http://www.tandfonline.com/doi/full/10.1080/07391102.2017.1289124

DOI: 10.1080/07391102.2017.1289124

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