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In: Biology

In order to study the EGF receptor you engineer a protein that can bind ligand but...

In order to study the EGF receptor you engineer a protein that can bind ligand but lacks the intracellular domain of the protein. If you overexpress this protein in the cell it acts like a dominant negative. Explain how it might bind with normal receptors and inhibit downstream signaling. Rubric: Explain how the dominant negative interacts with cellular components (.5) and how this interaction will overall inhibit EGFR signaling (.5).

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Answer)

The extracellular domain of all Notch proteins contains 29–36 tandem Epidermal growth factor (EGF)-like repeats, some of which interacts with ligands. These interaction with ligand presented by neighboring cells (trans interactions) are mediated by repeats 11–12 (whereas inhibitory interaction with ligand co-expressed in the same cell (cis interactions) are mediated by repeats 24–29. Many EGF repeats bind calcium that plays an important role in determining the structure and affinity of Notch to its ligands.

The EGF repeats are followed by a negative regulatory region (NRR) composed of three cysteine-rich Lin12-Notch repeats (LNR) and a heterodimerization domain (HD). The NRR plays a critical role in preventing receptor activation in the absence of ligand. Most surface Notch proteins are cleaved by furin-like convertases at site 1 (S1) located within an unstructured loop protruding from the HD subdomain, thereby converting the Notch polypeptide into an NECD-NTMIC (Notch extracellular domain-Notch transmembrane and intracellular domain) heterodimer held together by non-covalent interactions between the N- and C-terminal halves of HD. S1 cleavage likely occurs in the secretory pathway as secreted NRR modules undergo S1 cleavage. However, the presence of less stable, uncleaved Notch molecules at the cell surface is also consistent with convertase cleavage occurring after receptor recycling.


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