handout16 - Protein Folding BACKGROUND(Annsens Dogma The...

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Protein Folding BACKGROUND: (Anfinsen’s Dogma) The three dimensional structure of a protein is largely defined by its amino acid sequence. If you place an unfolded protein into solution, it will spontaneously fold. The system is moving towards the state of lowest free energy. The stability of a water soluble, globular protein depends on a number of factors: The unfolded state is entropically favoured (many more unfolded than folded states) Folding is enthalpically favoured (hydrogen bonds, hydrophobic effect in which hydrophobic residues are often buried i.e. shielded from the solvent) fi When a soluble protein unfolds, water forms structured ’cages’ around the nonpolar residues, which is entropically unfavourable. NOTE: These general rules are different for membrane proteins (tend to be ’inside out’ – hydrophobic residues are exposed to favourably interact with the membrane lipids) NOTE: Not all proteins will fold by themselves. Some need some help to fold at all, or refold in a crisis such as heat shock. there are proteins that help other proteins fold: chaperones . 4–78
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EXAMPLE: One of the most intensively studied chaperone systems is the GroEL/GroES system . Consists of two proteins, both are essential for the E.coli bacteria. Barrel-like arrangement with seven-fold symmetry (PDB code 1WF4) GroEL (red, orange pink) 14 subunits GroES (blue,green), 7 subunits, forms a removable cap of the barrel. GroEs binds to either end of GroEL in the presence of Adenosine-5’-triphosphate (ATP). 4–79
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PROBLEM: An unfolded protein will often expose hydrophobic residues. This can lead to aggregation of these unfolded proteins which prevents them from folding. SOLUTION: GroEL/GroES encapsulates one unfolded protein at a time to prevent aggregation. It attracts the unfolded protein by exposing hydrophobic residues, then changing the internal environment into one less hydrophobic to stimulate folding. ADP ADP ATP ATP C ATP ATP D A B ADP ADP ATP ATP [groel-groesreview98.pdf] A a single partly folded protein binds to hydrophobic residues at an open end of the barrel. A GroES cap is closes the cavity because of the ATP present. A conformational change within the cavity leads to a burying of the hydrophobic GroEL residues from the protein. This induces folding of the protein. B ATP is hydrolised to ADP within 10-15s, leading to weakening of the GroEL/GroES complex. C ATP is bound to the opposite chamber, causing GroES to 4–80
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dissociate. The folded protein is released. D The cycle begins again (shown in dashed form), but now GroES binds to the opposite end of the barrel. QUESTION: How can we measure protein stability? ANSWER: It is possible to unfold or denature a protein by increasing the temperature, changing pH or by addition of organic solvents such as urea or guanidinium chloride. Recently, it has also become possible to unfold single protein molecules by pulling it apart (Atomic Force Microscopy –AFM).
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