CellBio_Lecture3_ProteinFoldingDegradation.docx - PROTEIN...

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PROTEIN FOLDING AND DEGRADATION Folding of a protein is controlled by its amino acid sequence involving mostly the four types of non- covalant interactions between the backbone and r groups of pairs of amino acids. They fold into the conformation of lowest energy. Polar side chains on the surface, non polar on the inside. Hydrophobic interactions. Some of the proteins begin to fold as they are synthesized. For such proteins after a “domain” emerges from the ribosome, it can take as little as a few seconds to form a compact structure that contains most of the final secondary structure. Nascent proteins fold (often quickly) into an initial structure (molten globule) that then matures into the final conformation. Formation of the mature conformation is generally much slower than the initial folding process. Some proteins require the binding of cofactors (ex. Zn++) other proteins and/or covalent modifications to fold into their mature conformation. We have the Zinc finger that links a cysteine to a histidine. Most properly folded proteins (that have associated with appropriate partner proteins) do NOT have sizable exposed patches of hydrophobic amino acids on its surface. Hence, the presence of a lot of exposed hydrophobic residues is often indicative of a misfolded or partially folded protein. Several types of molecular chaperones help proteins fold in a cell. 2 major types: Monomer HSP70 and Polymer HSP60 Each works with it’s own set of accessory proteins to help other proteins fold. Both have an affinity for exposed hydrophobic patches (4-5 amino acids) on incompletely folded proteins Both bind and hydrolyze ATP HSP 70 is used as the protein is being synthesized. It binds to multiple sites on a target protein with ATP. It folds the protein and loses a phosphate. Then release ADT and ATP helps release the hsp70 machinery. Then the protein is either folded correctly YAYYYY or not, in which case hsp70 bound with ATP binds to the protein again. Make take multiple cycles to fold a single protein correctly. By binding stretches of hydrophobic residues it prevents mis-folding and nonspecific hydrophobic interactions. HSP 60 is multimeric and acts later. The entire protein has been made. It has many exposed hydrophobic stretches. They are recruited to the HSP 60 chaperone because there are binding sites for hydrophobic stretches. ATP binds and the cap closes the complex. Lining the inner surface are multiple binding sites for hydrophobic stretches. multiple round of ATP hydrolysis result in the correctly folded protein. ADP is released, ATP binds and cap opens. Correctly folded protein is released.
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