Sandbox Reserved 813: Difference between revisions

<scene name='56/568011/Linker/1'>The linker</scene> tethers the two POU subdomains and is hypervariable in both sequence and length. Thus the linker in Oct-4 contrary to the linker of the other member of the POU family like Oct-1 [http://en.wikipedia.org/wiki/POU2F1], is a 17 amino acid  alpha-helix and is exposed to the protein surface. The Oct4 linker functions as a '''protein-protein interaction''' interface and plays a highly important role during '''reprogramming'''. This alpha 5 helix interacts with helices alpha 2 and alpha 4 of POUs mostly by Van der Waals interaction, except for the hydrogen bond between<scene name='56/568011/Liaison_25-81/1'>Tyr 25 of POUs and Gln 81</scene> of the linker. The interaction between Val 36 of POUs and the the carboxy-terminal of the helix alpha 5 of the linker plays an important role. In all known Oct-4 sequences <scene name='56/568011/Asn79_and_leu80/1'>Asn79 and Leu80 </scene> are invariant but not conserved in other members of Oct family.  Mutation in the linker of GLn81 by an Arg leads to a complete loss-of-function phenotype. Likewise mutation of Leu80 by an Ala abolished biological activity. It is deduced that this mutation disturbs an interaction surface with yet unknown additional factors. Overall mutation of the linker of the protein lead <scene name='56/568011/Asn76_asn_77_asn_79/1'>residues exposed to the surface</scene>(Asn76, Asn 77, Asn 79)  to significantly fewer function. The integrity of the linker is essential for successful reprogramming.

The <scene name='56/568011/Pouhd/1'>homeodomain</scene> (POUhd) is a very conserved 60 amino acid '''three helices alpha DNA-binding domain'''. We can find the homeodomain form the 223th to the 282th amino acid in the Oct-4 sequence.Its DNA sequence is called the “homeobox”, and the genes are known as “Hox gene”. The DNA recognition helix (alpha 3) binds the DNA major groove while the amino-terminal tail binds the DNA minor groove. We can draw a parallel with oct1 and oct2  about the Homeodomain and admit that the ninth residue of the DNA-recognition helix is a cysteine that might have been conserved at this position to confer DNA binding specificity , and promote more relaxed DNA sequence recognition by POU domains. The recognition helix and the inter-helix loops are rich in arginine and lysine residues, which form hydrogen bonds to the DNA backbone.  

Oct-4 is able to create a complex with Sox-2 to express genes involved in the embryonic development such as YES1. Oct-4 is also involved in the creation of intestinal and skin cancer. Indeed, the overexpression of Oct-4 provokes the upregulation of B-catenin [http://en.wikipedia.org/wiki/Beta-catenin] transcription which inhibit the cellular differentiation.

Oct-4, Sox2, [[c-Myc]] and Klf4 are the four factors involved in the '''cell reprogamming'''. Indeed, those four factors  were used in the Yamanaka’s studies to reprogram mature cells in '''inducted pluripotent stem cells''' ([http://fr.wikipedia.org/wiki/IPS iPS] )and are thus also named “Yamanaka factors”. When they are in a mature cell, they can induce the expression of genes involved in the reprogramation of cells in an embryonic-state:  cells which possess the same morphology and the same growth properties than embryonic stem cells. The unique structure of the linker domain between the POU-specific domain and the Pou-homeodomain gives Oct-4 a protein very important for the study of iPS cells . Indeed, the others transcription factors are recruited and a complex is created with the linker domain.  

*[http://genesdev.cshlp.org/content/5/6/897.full.pdf+html]'''POU-domain transcription factors: pou-er-ful developmental regulators.''' M G Rosenfeld ''Genes Dev. 1991 5: 897-907''

*[http://www.nature.com/ncb/journal/v15/n3/full/ncb2680.html]'''A unique Oct4 interface is crucial for reprogramming to pluripotency''' : Daniel Esch,Juha Vahokoski,Matthew R. Groves,Vivian Pogenberg,Vlad Cojocaru,Hermann vom Bruch,Dong Han,Hannes C. A. Drexler,Marcos J. Araúzo-Bravo,Calista K. L. Ng,Ralf Jauch,Matthias Wilmanns& Hans R. Schöler ''Nature Cell Biology 15,295–301(2013)''

*[http://www.ncbi.nlm.nih.gov/pubmed/16451351]'''Embryonic Stem Cells: Similarities and Differences Between Human and Murine Embryonic Stem Cells'''Sonja Koestenbauer1, Nicolas H. Zech2, Herbert Juch1, Pierre Vanderzwalmen3, Luc Schoonjans4,

*[http://www.ncbi.nlm.nih.gov/pubmed/23376973] '''A unique Oct4 interface is crucial for reprogramming to pluripotency'''Daniel Esch1,5, Juha Vahokoski2,5, ''NATURE CELL BIOLOGY VOLUME 15 j NUMBER 3 j MARCH 2013''

*[http://genesdev.cshlp.org/content/9/14/1679.refs.html] '''The POU domain: versatility in transcriptional regulation by a flexible two-in-one DNA-binding domain'''Winship Herr 1 and Michele A. Cleary 1'2''GENES & DEVELOPMENT 9:1679-1693 9 1995''

*[http://www.ncbi.nlm.nih.gov/pubmed/2905684]'''The ubiquitous octamer-binding protein Oct-1 contains a POU domain with a homeo box subdomain''' Richard A. Sturm, Gokul Das, and Winship Herr''GENES & DEVELOPMENT 1988''