Williams BCH 444 2014 Lectures 3-6

Williams BCH 444 2014 Lectures 3-6 - BCH 444 Spring 2014...

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• Targeting nascent proteins to the endoplasmic reticulum • Protein translocation into the ER, membrane protein topology • Protein glycosylation, functions of glycoproteins • Protein folding in the ER, role of chaperones and folding catalysts • Protein quality control - ERAD and the UPR David B. Williams, Room 5316 MSB [email protected] BCH 444 Spring 2014 1
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2 Endoplasmic Reticulum (ER) - first stage in the secretory pathway - About 30% of cellular proteins are synthesized on membrane-bound ribosomes of the ER and are translocated partially (membrane proteins) or completely (soluble proteins) across the ER membrane. - This segregates them from other cellular proteins and establishes their topology as transmembrane or soluble proteins - These proteins are subsequently sorted to their final destinations as they move along the secretory pathway from ER to Golgi to cell surface
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Functions of the Endoplasmic Reticulum Identification of incompletely folded or misfolded proteins Retention of incompletely/misfolded proteins within the ER Disposal of misfolded proteins - ER-associated degradation (ERAD) Signaling the presence of misfolded proteins to the nucleus - the unfolded protein response (UPR) Export of properly folded proteins along secretory pathway. - Ca 2+ storage, uptake and release (primary cellular calcium store) - Lipid biosynthesis - phospholipids, cholesterol, glycosphingolipids - Protein biogenesis Protein folding Post-translational modifications, e.g., glycosylation, disulfide bonds (oxidizing environment), cis-trans proline isomerization Protein quality control ± ± 3
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4 1 2 3 4 5 Stages in the targeting of nascent proteins to the ER 1. Proteins destined for the ER are synthesized (usually) with an N-terminal signal sequence 2. Signal is recognized by Signal Recognition Particle (SRP) 3. SRP binds to SRP receptor on ER membrane - (brings translating polyribosome to the ER). SRP receptor helps target the ribosome to the translocon pore. 4. SRP is released, ribosome binds to translocon, nascent chain enters translocon. 5. Nascent polypeptide is translocated into the ER lumen and signal is removed by signal peptidase “free” ribosomes “membrane-bound” ribosomes
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5 Günter Blobel, Nobel Laureate, 1999 Fundamental question addressed: • How are proteins that are synthesized on membrane-bound ribosomes and that enter the ER (proteins of the secretory pathway) distinguished from other nascent proteins? The Signal Hypothesis - Günter Blobel 1971 - 1975
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6 Basis for the original Signal Hypothesis in 1971 What was known at the time: • mRNAs for some secretory proteins are translated on membrane-bound ribosomes (rough ER) whereas mRNAs for some cytosolic proteins are translated on free polyribosomes.
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Williams BCH 444 2014 Lectures 3-6 - BCH 444 Spring 2014...

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