Marcu Lecture 6

Marcu Lecture 6 - Marcu Lecture 6 Slide 95, 96 -...

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Marcu Lecture 6 Slide 95, 96 - Transcriptional activators of the nfkb family - Two of them have built into their CTD an inhibitory domain - Inhibiroty domain Must be procecssed away from the amino terminus because if this protein as it is complexes with one of these and makes a dimer with It, it will stay in the cytoplasn keep it in the cytoplasm - You have to remove the inhibitor to liberate the function part ofor transcription of the DNA binding domaing (the rel homology domain) o Highly conserved in the family - DNA will bind to slightly different sequence the same overall general sequence - Only bind to DNA effectively as a dimer and not monomers - Can bind in any combination of these five proteins - There is also another family of genes that encode inhibitors only o The ikb alpha gene, ikb beta gene, ikb epsilon gene o Resembles an inhibitor but really is not- BCL-3 gene - Two possible sites for phorphorylation of the amino terminus of all 3 proteins - When the phosphprylation happens, it targets [these] proteins for subsequent lysine ubiquination by ligases of the the proteosome complex which destroys them, which is very important how these things leave the cytoplasm into the nucleus - All of these proteins are always held in the cytoplasm in a dormant state or in check - Either one of these complexed to the precursor proteins - you hae to remove from the complex to get relocation to the nucleus - happens in response to signals coming from the outside of the cell - all color combinations (flavors) are possible - there is variation in what the Rel homology domains will bind too - Rela is also called p65 - Exclusivity in what target genes will be activated depending on who is in the dimer that is binding the DNA - Nfkb binding site Sequences are highly conserved between mouse and human - - Slide 98 - Phosphorylation exposes DNA binding domain of p65 - Many signals can activate somekind of kinase complex but it wasn’t known o Stress signals eg. Infection by bioorganism, responses from cytokines or chemokines, pH and osmolarity changes - NFKB family members, prototypical members are p50 attached to p65, and the inhibitor that is associated is always ikb alpha - Upon a signal, amino terminus end of the inhibitor got phosphorylated on two sites o Two serines very nearch each other o Very fast and Happens in minnutes
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- If you wait a little while longer, after phosphorylated, it gets recognized by the substarate and it ubiquinated and the inhibitor gets destroyed by proteosome - What proteosome does, and you can only ubiquinate nearby lysines if phosphorylated - In the absense of the inhibitor the nfkb dimer can pass through the nuclear pore and DNA and might activate trassncription - The reason why it cant get into the nucleus is that there is a nuclear localization signal of aminoacids embeded in the p65 component which is hidden by the inhibitor - Importins recognize exposed sequenes tohelp bring it to the nucleus - “maybe” activate transcription o Its tru that it will bind DNA, but it might not activate transcription
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Marcu Lecture 6 - Marcu Lecture 6 Slide 95, 96 -...

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