GENE 500 Lecture Notes - Lecture 4: Energy Landscape, Protein Folding, Ribonuclease
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Lecture 4 - Number of Proteins
Correcting Misfolded Proteins
• Although a small protein like ribonuclease
can fold spontaneously, even it is slow by
biological standards
• In the cell, protein folding is assisted by
chaperones and chaperonins
• Chaperones help move proteins to and
between energy states
• Energy landscape limited by co-translation
• Solvent is part of the process; in aqueous
medium, hydrophobic residues form the internal
core
Step 1: When bound to ATP, the monomeric
Hsp70 protein assumes an open conformation, in
which an exposed hydrophobic substrate-binding
pocket transiently binds to exposed hydrophobic
regions of an incompletely folded or partially
denatured target protein, and then rapidly
releases this substrate, as long as ATP is bound
Step 2 & 3: Hydrolysis of the bound ATP causes the molecular chaperone to assume a closed
form that binds its substrate protein much more tightly, and this tighter binding appears to
facilitate the target protein’s folding, in part by preventing it from aggregating with other
unfolded proteins; induces a large conformational change in the substrate-binding domain,
resulting in the closed conformation, in which the substrate is locked into the substrate-binding
domain; here proper folding is facilitated
Step 4 & 5: Exchange of ATP for the bound ADP, stimulated by other accessory cochaperone
proteins (GrpE/BAG1), converts the Hsp70 back to the open conformation, releasing the
properly folded substrate and regenerating the open conformation, which can then interact
with additional substrates