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Ligand Binding and the Cell Cycle .docx

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BIOL 3096
Joel Sheffield

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Lecture 37 – Ligand/Receptor Interactions November 22, 2013 Ligand Mediated Dimerization 1. Aligand with two binding sites binds two inactive monomers, activating them as a dimer 2. The activated monomers trans-autophosphorylate each other. 3. The phosphorylated region binds to another protein, which is referred to as the SH do2ain, (the term SH 2tems from Sarc Homology, sarc being one of the first viral genes found to induce cancer, from the sarcoma virus) 4. The SH re2ion catalyzes further kinase reactions in the cell. Receptor Mediated Dimerization 1. Aligand binds to a single monomer, which causes a conformational change in the monomer, causing it to bind to another ligand bound monomer. 2. This creates an active dimer, which then proceeds as described in the Ligand Mediated model. Example of a Receptor Kinase (AG-Protein) 1. Growth factor (ligand) binds to a tyrosine receptor kinase, which activates the kinase and allows it to phosphorylate the receptor (Although 3 amino acids can be phosphorylated; Serine threonine and tyrosine, receptor molecules seem to only use phosphorylation on tyrosine). 2. Phosphorylation of the receptor is results in its activation. 3. The receptor causes several reactions which result in the phosphorylation of Ras-GDP (ras is another viral protein) 4. This phosphorylates Soluble Raf to form membrane-bound Raf (called MAPKKK, K=Kinase) 5. MAPKKK phosphorylates MEK to make MAPKK 6. MAPKK phosphorylates ERK to make MAPK 7. MAPK phosphorylates the transcription factor activating it and allowing mRNAproduction. 8. Thus in each step the process is amplified. Insulin Receptor- G-Protein • Ligand is insulin 1. Receptor is already coupled, when insulin binds it causes the receptor to be phosphorylated 2. Other proteins bind to the receptor, and eventually lead to a cascade that includes Ras-GTP and a process much like the one above. Frizzled Receptor • Ligand is Wnt ◦ First discovered as the integration gene for mammary tumors in mice, it was called Int ◦ About the same time a gene was found to produce a wingless phenotype in Drosophila, it was called wingless. ◦ These turned out to be the same gene, and it was renamed Wnt, merging both names. • The Frizzled Receptor was first found in Drosophila 1. Wnt activates the Frizzled Receptor 2. The receptor activates a protein called Disheveled (Dsh) 3. Dsh interacts with a protein complex that includes β-catenin (a protein that was first found to interact with cadherin at the ends of certain junctional fiber structures and was thought to only be involved in cytoskeletal control). 4. β-catenin is isolated from the complex, so the concentration of the pure protein becomes higher in the cell and enters the nucleus, where it activates a whole set of genes involved in cell behavior. 5. From this, it has been established that Wnt plays a significant role in embryog
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