Structural basis for nuclear import selectivity of pioneer transcription factor SOX2

Bikshapathi Jagga, Megan Edwards, Miriam Pagin, Kylie M. Wagstaff, David Aragão, Noelia Roman, Jeffrey D. Nanson, Shane R. Raidal, Nicole Dominado, Murray Stewart, David A. Jans, Gary R. Hime, Silvia K. Nicolis, Christopher F. Basler and Jade K. Forwood ()
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Bikshapathi Jagga: Charles Sturt University
Megan Edwards: Georgia State University
Miriam Pagin: University of Milano-Bicocca
Kylie M. Wagstaff: Monash University
David Aragão: Harwell Science and Innovation Campus
Noelia Roman: Charles Sturt University
Jeffrey D. Nanson: University of Queensland
Shane R. Raidal: Charles Sturt University
Nicole Dominado: University of Melbourne
Murray Stewart: Cambridge Biomedical Campus
David A. Jans: Monash University
Gary R. Hime: University of Melbourne
Silvia K. Nicolis: University of Milano-Bicocca
Christopher F. Basler: Georgia State University
Jade K. Forwood: Charles Sturt University

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: Abstract SOX (SRY-related HMG-box) transcription factors perform critical functions in development and cell differentiation. These roles depend on precise nuclear trafficking, with mutations in the nuclear targeting regions causing developmental diseases and a range of cancers. SOX protein nuclear localization is proposed to be mediated by two nuclear localization signals (NLSs) positioned within the extremities of the DNA-binding HMG-box domain and, although mutations within either cause disease, the mechanistic basis has remained unclear. Unexpectedly, we find here that these two distantly positioned NLSs of SOX2 contribute to a contiguous interface spanning 9 of the 10 ARM domains on the nuclear import adapter IMPα3. We identify key binding determinants and show this interface is critical for neural stem cell maintenance and for Drosophila development. Moreover, we identify a structural basis for the preference of SOX2 binding to IMPα3. In addition to defining the structural basis for SOX protein localization, these results provide a platform for understanding how mutations and post-translational modifications within these regions may modulate nuclear localization and result in clinical disease, and also how other proteins containing multiple NLSs may bind IMPα through an extended recognition interface.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20194-0

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DOI: 10.1038/s41467-020-20194-0

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