Chaperones Overview PDF

**Chaperones Overview** - **Definition**: Proteins that assist in the proper folding of nascent (newly made) proteins and prevent aggregation. - **Importance**: Found in all organisms (from bacteria to humans), using similar mechanisms for protein folding. Many are evolutionarily c...

**Chaperones Overview** - **Definition**: Proteins that assist in the proper folding of nascent (newly made) proteins and prevent aggregation. - **Importance**: Found in all organisms (from bacteria to humans), using similar mechanisms for protein folding. Many are evolutionarily conserved. **Types of Chaperones** 1. **Molecular Chaperones**: Bind to short segments of unfolded proteins, preventing aggregation and stabilizing them. - **Example**: Hsp70 family (found in cytosol and mitochondria), BiP (Grp78 in ER), DnaK (in bacteria). - **Function**: Bind to hydrophobic regions of nascent proteins to prevent improper interactions or premature folding. 2. **Chaperonins**: Create a folding chamber, isolating the unfolded protein and allowing it to fold properly in a controlled environment. - **Function**: Sequester the protein inside a chamber to allow for proper folding. **Heat Shock Proteins (HSPs)** - **Function**: Upregulated in response to stress (e.g., heat, cold, chemicals). Protect cells by assisting in protein folding under adverse conditions. - **Key Examples**: Hsp70, upregulated during stress conditions like heat shock or exposure to toxins. - **Link to Aging**: HSP expression increases with age and in diseases like Huntington\'s and Alzheimer\'s. **Protein Folding Challenges** - **In Theory**: Proteins fold into their lowest energy, stable state (Anfinsen's Dogma). - **In Reality**: Folding in cells is complicated by stress, crowded environments, and competing interactions, requiring chaperones to assist. - **Competition**: Proteins can either fold correctly or misfold and aggregate. Chaperones help guide folding towards the native state. **Molecular Chaperones** - **Mechanism**: Assist protein folding by binding to hydrophobic regions, disrupting incorrect interactions and stabilizing correct ones. - **BiP (Grp78)**: Important in ER stress response and plays a role in diseases like **prostate cancer** (anti-apoptotic effects when bound to the NH2-terminal domain). **Chaperonin-Mediated Folding** - **Structure**: Chaperonins (like bacterial Group I or mammalian Group II) form multi-subunit chambers where proteins fold. ATP hydrolysis triggers the lid's opening and closing, allowing controlled folding within the chamber. **Protein Misfolding Diseases** - **α1-Antitrypsin Deficiency (AATD)**: Misfolding leads to impaired liver and lung function, causing diseases like emphysema and cirrhosis. - **Prostate Cancer**: Misfolding linked to the effects of BiP, leading to proliferation or apoptosis depending on the region targeted.