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Cellular Stress Adaptation and the Origins of Disease

1The Logic of Cellular Stress and Adaptation2Stress Sensing and Signal Transduction3Proteostasis: Folding, Chaperones, and Degradation4ER Stress and the Unfolded Protein Response5Mitochondrial Stress, Quality Control, and Cell Fate6Metabolic and Nutrient Stress Adaptation7Inflammatory and Immune Stress Signaling8When Adaptation Becomes Disease: Transition Mechanisms9Disease Applications and Therapeutic Targeting
Proteostasis: Folding, Chaperones, and Degradation

Why a protein folds, and why it sometimes does not

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Think about what it means for a protein to be stable but not folded. The native state is the lowest-energy conformation, so at equilibrium the folded protein is favored. But a newly made chain has to get there through a funnel of partially folded intermediates, and those intermediates expose hydrophobic patches that are normally buried. If two such patches meet, they can stick, and the resulting aggregate is often trapped. Chaperones do not add energy to push the chain toward the native state. They bind exposed hydrophobic segments, block those inappropriate contacts, and give the client another chance to fold. Because binding is stoichiometric, the number of chaperone molecules available sets a hard ceiling on how much misfolded protein can be managed at once. That ceiling is the variable that drives everything else in this chapter.
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Stability is thermodynamic; folding is kinetic

The native state is the conformation with the lowest free energy under cellular conditions, so the folded protein is favored at equilibrium. That thermodynamic fact does not tell you whether the protein will actually get there. A polypeptide must traverse a folding funnel in which partially folded intermediates expose hydrophobic side chains that are normally buried in the native structure. Those exposed surfaces can associate with each other, and because the resulting aggregate is often kinetically trapped, the cell can end up with a stable but non-functional deposit even though the native state is thermodynamically preferred.

What chaperones actually contribute

Chaperones bind exposed hydrophobic segments and shield them from inappropriate contacts. They do not push the polypeptide toward the native state by adding energy; they reduce the competing aggregation reaction and give the client repeated opportunities to fold. Because binding is stoichiometric and transient, the number of available chaperone molecules sets a ceiling on how much misfolded client can be managed at once. When that ceiling is reached, the excess client is left exposed, and aggregation becomes the dominant outcome.

The capacity limit is the central variable

Every later section of this chapter is a variation on one question: what happens when the load of misfolded protein exceeds the capacity of the machinery available to handle it? Chaperone-assisted folding is the first line of defense, but it is saturable. The next two pages describe the two degradation routes the cell uses when refolding fails.

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