10.8
Molecular Chaperones and Protein Folding
As they are synthesized in the cell, most proteins do not fold spontaneously into their native conformation but require a special class of proteins called chaperones to help fold them.
Of the several types of molecular chaperones found in prokaryotes and eukaryotes, the two major families are the heat shock proteins - hsp70 and hsp60.
In a correctly folded protein, hydrophobic patches are buried in the interior.
In misfolded proteins, hydrophobic patches are exposed. Such patches on different protein molecules can bind to each other, leading to irreversible protein aggregation.
Chaperones recognize these exposed hydrophobic patches and prevent protein aggregation, facilitating the folding of the proteins.
The hsp70 machinery often acts before the protein leaves the ribosome, with each ATP-bound monomer recognizing a small stretch of hydrophobic amino acids on a protein’s surface.
A set of smaller hsp40 proteins interacts with this complex and triggers ATP hydrolysis. As a result, parts of hsp70 come together like jaws, trapping the unfolded protein inside.
Next, ATP binds the complex again inducing the dissociation of hsp70 and releasing the bound polypeptide, allowing it a chance to re-fold. If folding does not occur rapidly enough, the polypeptide may bind again, and the process is repeated until the protein is folded into its native conformation.
Alternatively, a fully synthesized and partially folded polypeptide may be delivered to a chaperonin.
Chaperonins are large barrel-shaped protein complexes that provide an isolated chamber for protein folding, with one half of the symmetric barrel operating on a client protein at a time.
In E. coli, the chaperonin system is called GroEL/GroES, while its eukaryotic analog is called Hsp60.
A misfolded protein is captured by hydrophobic interactions with the exposed surface of the opening. This initial binding often helps to unfold a misfolded protein.
Once the protein is inside, ATP binding seals the chamber with a cap.
The interior of the chamber is lined with hydrophilic surfaces, where the protein can fold in isolation.
ATP hydrolysis weakens the binding of the cap and binding of additional ATP molecules ejects the cap.
The substrate protein, whether folded or not, is released from the chamber.
The native conformation of a protein is formed by interactions between the side chains of its constituent amino acids. When the amino acids cannot form these interactions, the protein cannot fold by itself and needs chaperones. Notably, chaperones do not relay any additional information required for the folding of polypeptides; the native conformation of a protein is determined solely by its amino acid sequence. Chaperones catalyze protein folding without being a part of the folded protein.
The unfolded or partially folded polypeptides, which are often intermediates in the folding pathway, are stabilized by chaperones, leading to the final correctly folded state. Without chaperones, the unfolded or partially folded polypeptides may misfold or form insoluble aggregates. This is particularly observed in proteins in which the carboxy or C-terminus is required for the correct folding of the amino or N-terminus. In such cases, a chaperone can bind and stabilize the N-terminal part of the polypeptide in an unfolded conformation until the rest of the peptide chain is synthesized and the whole protein can fold correctly.
Chaperones can also stabilize unfolded polypeptide chains as they are transported into subcellular organelles. For instance, during the transfer of proteins into the mitochondria from the cytosol, it is easier for partially unfolded conformations to be transported across the mitochondrial membrane. During the transport, the partially unfolded polypeptides are stabilized by chaperones.
Additionally, chaperones play an important role in the assembly of proteins that have a complex structure, such as multi-subunit proteins. These proteins comprise multiple polypeptide chains - each of which needs to be correctly folded and then assembled in a specific manner. In the processes involved, chaperones assist in protein folding and the stabilization of unassociated components while other parts of the protein are undergoing assembly.
As they are synthesized in the cell, most proteins do not fold spontaneously into their native conformation but require a special class of proteins called chaperones to help fold them.
Of the several types of molecular chaperones found in prokaryotes and eukaryotes, the two major families are the heat shock proteins - hsp70 and hsp60.
In a correctly folded protein, hydrophobic patches are buried in the interior.
In misfolded proteins, hydrophobic patches are exposed. Such patches on different protein molecules can bind to each other, leading to irreversible protein aggregation.
Chaperones recognize these exposed hydrophobic patches and prevent protein aggregation, facilitating the folding of the proteins.
The hsp70 machinery often acts before the protein leaves the ribosome, with each ATP-bound monomer recognizing a small stretch of hydrophobic amino acids on a protein’s surface.
A set of smaller hsp40 proteins interacts with this complex and triggers ATP hydrolysis. As a result, parts of hsp70 come together like jaws, trapping the unfolded protein inside.
Next, ATP binds the complex again inducing the dissociation of hsp70 and releasing the bound polypeptide, allowing it a chance to re-fold. If folding does not occur rapidly enough, the polypeptide may bind again, and the process is repeated until the protein is folded into its native conformation.
Alternatively, a fully synthesized and partially folded polypeptide may be delivered to a chaperonin.
Chaperonins are large barrel-shaped protein complexes that provide an isolated chamber for protein folding, with one half of the symmetric barrel operating on a client protein at a time.
In E. coli, the chaperonin system is called GroEL/GroES, while its eukaryotic analog is called Hsp60.
A misfolded protein is captured by hydrophobic interactions with the exposed surface of the opening. This initial binding often helps to unfold a misfolded protein.
Once the protein is inside, ATP binding seals the chamber with a cap.
The interior of the chamber is lined with hydrophilic surfaces, where the protein can fold in isolation.
ATP hydrolysis weakens the binding of the cap and binding of additional ATP molecules ejects the cap.
The substrate protein, whether folded or not, is released from the chamber.
From Chapter 10:
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10.8 : Molecular Chaperones and Protein Folding
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