OCT 4 cell differentiation
transcription factor
Boyu Yang '22 and Maopeli Ali '21
Contents:
I. Introduction
Oct4 is a POU family member specific to the mammalian germline, encoding a transcription factor that is found in oocytes and is zygotically expressed in pluripotent cells of the pre gastrulation embryo. POU proteins are eukaryotic transcription factors containing a bipartite DNA binding domain. POU domain genes have been described in various organisms and have shown to have a wide variety of functions, all of which are related to the function of the neuroendocrine system and the development of an organism. Research of Oct-4 expression in mice has shown that it is vital for regulating pluripotency and early cell differentiation since one of its main functions is to keep the embryo from differentiating and may serve as a recruiting platform during the epigenetic transition from a differentiated to a pluripotent cell state. The POUs and POUhd domain are highly conserved structures but there is variability in the structure of the N and C-terminal
II. General Structure
OCT4 is comprised of two subdomains: a POU-specific domain POUs
with four α-helices consisting of 151 residues and a POU homeodomain POUhd with three α-helices consisting of 150 residues. POU-specific domain makes the sequence-specific protein DNA interactions and has an N-terminal subunit, whereas the POU homeobox domain has a C-terminal subunit. Both subdomains contain the structural motif 'helix-turn-helix', which directly associated with the two components of DNA binding sites, and are required for high-affinity sequence-specific DNA-binding.
These two subdomains are tethered by a linker region through van der Waal and hydrogen bond interaction at its terminals. The amino acids of helix α5 are also highly conserved in other Oct4 orthologues. The OCT4 linker can not be replaced by other POU factors which emphasizes the importance of the linker. Research has shown the linker region functions as a protein-protein interaction interface and plays a crucial role during reprogramming by recruiting key epigenetic players to Oct4 target genes.
III. Protein-Protein interaction
Within these domains, Transcription is highly dependent on the interaction strength between the linker and those two POU subunits. Linker region tethers the two subdomains. Alpha-helix5 on the linker interacts with helices2 and3 of the POUs, mostly by Van der Waal interactions, except for one specific hydrogen bond between Tyr25 of the POUs and of the linker. The of the POUs plays a prominent role by interacting with the carboxyl-terminal part of the linker alpha 5. Researchers tried to understand the importance of the linker region within the OCT4 system. Researchers made three variant strains of OCT4 using other POU linker factors in OCT6/OCT1 and found that linker had a reduction in transcription activity or a complete loss-of-function phenotype.
IV. Protein-DNA Interaction
Due to a lack of research, there is little knowledge on the specific order protein-DNA interaction. However, research has shown that POUs proteins bind as monomers to the so-called octamer motif of DNA or form distinct homodimers based on the pseudo-palindromic PORE and the palindromic MORE sequence motifs. The Helix A+B residues: Q146,N143, R97 V139, R49T45, Q44(helix B) interacts with the PORE sequence motif (ATG A/T AAT). The POUhd can make non-specific DNA-protein interactions with the DNA. Both the subdomains from non-polar interactions with phosphate backbone
| Protein atom |
Interaction Chain |
Interaction base |
Button |
| Q146 |
A chain |
#6A |
|
| N143 |
A chain |
#18A |
|
| R97 |
A chain |
#A/#16A/#10G |
|
| V139 |
B chain |
#20T |
|
| R49 |
A chain |
#10G |
|
| T45 |
A chain |
#11A/#13T |
|
| Q44 |
B chain |
#13A |
|
V. References
Reményi, A. et al. Crystal structure of a POU/HMG/DNA ternary complex suggests differential assembly of Oct4 and Sox2 on two enhancers. Genes Dev. 17, 2048–2059 (2003).
Klemm, J.D., Rould, M.A., Aurora, R., Herr, W., and Pabo, C.O. 1994. Crystal structure of the Oct-1 POU domain bound to an octamer site: DNA recognition with tethered DNA-binding modules. Cell 77: 21–32.
Esch, Daniel, et al. “A Unique Oct4 Interface Is Crucial for Reprogramming to Pluripotency.” Nature Cell Biology, vol. 15, no. 3, Mar. 2013, pp. 295–301., doi:10.1038/ncb2680.
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