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Structure. 2014 Sep 2;22(9):1274-1286. doi: 10.1016/j.str.2014.06.014. Epub 2014 Aug 7.

Structural basis for the SOX-dependent genomic redistribution of OCT4 in stem cell differentiation.

Author information

1
Computational Structural Biology Group, Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany; Center for Multiscale Theory and Computation, Westfälische Wilhelms University, Correnstrasse 40, 48149 Münster, Germany.
2
Laboratory for Structural Biochemistry, Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore.
3
Genome Regulation Laboratory, Guangzhou Institutes for Biomedicine and Health, Chinese Academy of Sciences, 190 Kai Yuan Avenue, Science Park, 510530 Guangzhou, China.
4
Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany; Medical Faculty, Westfälische Wilhelms University, Domagstrasse 3, 48149 Münster, Germany.
5
Laboratory for Structural Biochemistry, Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore; Genome Regulation Laboratory, Guangzhou Institutes for Biomedicine and Health, Chinese Academy of Sciences, 190 Kai Yuan Avenue, Science Park, 510530 Guangzhou, China. Electronic address: ralf@gibh.ac.cn.
6
Computational Structural Biology Group, Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany; Center for Multiscale Theory and Computation, Westfälische Wilhelms University, Correnstrasse 40, 48149 Münster, Germany. Electronic address: vlad.cojocaru@mpi-muenster.mpg.de.

Abstract

In pluripotent cells, OCT4 associates with SOX2 to maintain pluripotency or with SOX17 to induce primitive endoderm commitment. The OCT4-SOX2 and OCT4-SOX17 combinations bind mutually exclusive to two distinct composite DNA elements, known as the "canonical" and "compressed" motifs, respectively. The structural basis for the OCT4-SOX17 cooperativity is unknown. Whereas SOX17 has been engineered to replace SOX2 in the pluripotency circuitry, all generated SOX2 mutants have failed to act like SOX17. From molecular simulations, we revealed the OCT4-SOX17 interaction interface and elucidated the SOX-dependent motif preference of OCT4. Moreover, we designed a SOX2 mutant that we predicted and confirmed experimentally to bind cooperatively with OCT4 to the compressed motif. Ultimately, we found a strong correlation between the experimental and calculated relative cooperative-binding free energies of 12 OCT4-SOX-DNA complexes. Therefore, we validated the OCT4-SOX interfaces and demonstrated that in silico design of DNA-binding cooperativity is suitable for altering transcriptional circuitries.

PMID:
25126959
DOI:
10.1016/j.str.2014.06.014
[Indexed for MEDLINE]
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