Crystal structure of a POU/HMG/DNA ternary complex suggests differential assembly of Oct4 and Sox2 on two enhancers.
Members of the POU and SOX transcription factor families exemplify the partnerships established between various transcriptional regulators during early embryonic development. Although functional cooperativity between key regulator proteins is pivotal for milestone decisions in mammalian development, little is known about the underlying molecular mechanisms. In this study, we focus on two transcription factors, Oct4 and Sox2, as their combination on DNA is considered to direct the establishment of the first three lineages in the mammalian embryo. Using experimental high-resolution structure determination, followed by model building and experimental validation, we found that Oct4 and Sox2 were able to dimerize onto DNA in distinct conformational arrangements. We demonstrate that the DNA enhancer region of their target genes is responsible for the correct spatial alignment of glue-like interaction domains on their surface. Interestingly, these surfaces frequently have redundant functions and are instrumental in recruiting various interacting protein partners.
Reményi
Attila
A
Gene Expression Program, EMBL, 69117 Heidelberg, Germany. remenyi@itsa.ucsf.edu
Lins
Katharina
K
Nissen
L Johan
LJ
Reinbold
Rolland
R
Schöler
Hans R
HR
Wilmanns
Matthias
M
D000818:Animals; D001483:Base Sequence; D002868:Chromosomal Proteins, Non-Histone; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000737:chemistry / Q000378:metabolism; D024002:HMGB Proteins; D006609:High Mobility Group Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism*; D009690:Nucleic Acid Conformation; D050814:Octamer Transcription Factor-3; D011487:Protein Conformation; D055748:SOXB1 Transcription Factors; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism; D014157:Transcription Factors; D015533:Transcriptional Activation
D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D024002:HMGB Proteins; D006609:High Mobility Group Proteins; D009687:Nuclear Proteins; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; C494174:Pou5f1 protein, mouse; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; C484738:UTF1 protein, human; C112198:Utf1 protein, mouse; C112971:fibroblast growth factor 14; D005346:Fibroblast Growth Factors; D004247:DNA