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LECT 21: REGULATED PROTEIN TURNOVER. Cellular proteins have different stabilities. It is the combination of synthesis and degradation rates that determines the level of a protein in a cell, and changes in either rate can serve as means to regulate
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LECT 21: REGULATED PROTEIN TURNOVER Cellular proteins have different stabilities. It is the combination of synthesis and degradation rates that determines the level of a protein in a cell, and changes in either rate can serve as means to regulate a protein’s concentration in the cell. Protein degradation in response to extracellular signals is an important component of some intracellular signaling pathways. Protein degradation is further required to mis-folded or de-folded proteins, which would otherwise be capable of forming insoluble aggregates.
Machinery for Protein Degradation Within Cells Cytosolic proteins targeted for degradation are digested in the 26S proteasome, a large multienzymatic structure. Membrane proteins targeted for degradation travel through endosomes to the lysosome, whose lumen contains a collection of proteases. Both targeting processes employ the covalent tagging of proteins with ubiquitin, a small 76 amino acid polypeptide.
Cbl Terminates Growth Factor Signaling Thru Receptor Ubiquination EGF EGF EGFR (inactive) EGFR (dimerized, phospho-Y) active POSITIVE SIGNALING SIGNAL TERMINATION Cbl (E3) Several pathways activated for growth or differentiation Internalization, ubiquitination, trafficking to lysosome
Ub Ub Ub Ub Ub Ub Proteasomal Degradation Can Activate Signaling Pathways: Transcription Via NFkB Extracellular Signal Proteasome Degradation IkB IKK E3 NFkB Nuclear Transport DNA Binding Transcription Activation
