2. Protein Folding

Folding in an Aqueous Environment

How does the complexity of the cytosol, a cellular fluid filled with proteins in various states, affect the folding of an individual protein?

One of the major problems for proteins in the aqueous environment is the risk of protein aggregation. Aggregates are multi-protein interactions that screw up the native fold and thus impede proper molecular function. Alzheimer’s Disease, for example, is due to aggregation of amyloid beta. Aggregates have a lower free energy than the native fold, which makes them even tougher to battle. This is called a kinetic trap.

The hydrophobic effect is a major factor in aggregation. Hydrophobic regions of different proteins strongly interact (entropy). Thus, the dominant intermolecular forces are similar to the dominant intramolecular forces.

Cells prevent aggregates through chaperons. These aid folding, prevent aggregation (hydrophobic interactions), and overcome kinetic traps.

HSP70 is a so-called heat-shock chaperon. It’s called heat shock because its expression increases under heat stress (HSP: heat shock protein). Recall that heat can lead to protein denaturing–a denatured protein is at a higher risk of aggregation.

HSP70 binds to nascent proteins before translation is complete and before it can aggregate. It interacts preferentially with hydrophobic residues, transiently masking them from other hydrophobic forces.

HSP70 has to release these regions when finished or it too will become an aggregator.

HSP70 is free while ATP-bound. When it’s ADP-bound, it starts working. This creates a loop from ATP-bound to ADP-bound and back and forth.

HSP60 is another heat-shock chaperon. This one is a barrel protein with a cage that envelops the nascent protein so that it can fold in peace.

Here’s a diagram of HSP60 at work…


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