Protein Folding and Molecular Chaperones

Protein folding is the process by which a newly made polypeptide adopts its specific three-dimensional structure, which is required for function. The information for folding is contained in the amino-acid sequence, but inside the crowded cell many proteins cannot fold reliably on their own. Molecular chaperones are proteins that bind unfolded or partly folded chains, prevent them from aggregating, and help them reach the native state.

Definition

Protein folding is the acquisition by a polypeptide of its native three-dimensional conformation, and molecular chaperones are proteins that assist this process by binding non-native states, preventing aggregation, and promoting correct folding, without being part of the final structure.

Scope

This topic covers the thermodynamic basis of folding, the folding energy landscape and the problem of aggregation, and the major chaperone systems (such as heat-shock proteins and chaperonins) that assist folding. It is a molecular reference and does not provide clinical guidance.

Core questions

• What determines the folded shape of a protein?
• Why is folding inside the cell harder than in dilute solution?
• How do chaperones help a chain fold without dictating its final structure?
• What happens when folding fails?

Key concepts

• Native conformation
• Folding energy landscape
• Hydrophobic collapse
• Aggregation and misfolding
• Molecular chaperones
• Heat-shock proteins (Hsp70, Hsp90)
• Chaperonins (GroEL/GroES, TRiC/CCT)
• Proteostasis

Key theories

Anfinsen's thermodynamic hypothesis

A protein's native structure is determined by its amino-acid sequence and is the conformation of lowest free energy under physiological conditions, so the folding instructions are intrinsic to the sequence.

Chaperone-assisted folding

In the crowded cell, chaperones do not contain folding information themselves but kinetically assist folding by transiently binding exposed hydrophobic regions of non-native chains, preventing aggregation and giving the protein repeated chances to reach its native state.

Mechanisms

Because the native fold is the lowest-free-energy state encoded by the sequence (Anfinsen, 1973), a polypeptide explores a funnelled energy landscape toward that state. The high protein concentration of the cytosol, however, makes exposed hydrophobic segments prone to aggregation. Chaperones such as the Hsp70 system bind these segments on nascent and stress-denatured chains, while chaperonins like GroEL/GroES and the eukaryotic TRiC/CCT enclose substrates in a chamber that favours productive folding; cycles of ATP-driven binding and release shield the chain until it reaches its native state (Hartl & Hayer-Hartl, 2002; Hartl et al., 2011; Kim et al., 2013).

Clinical relevance

When folding fails and proteins misfold or aggregate, the result can contribute to disease, and the chaperone network is part of the broader proteostasis system whose adjustment is studied as a route to intervention (Balch et al., 2008). This entry explains the normal mechanism and its general relevance and is not a basis for diagnosis or treatment.

History

Anfinsen's refolding experiments in the mid-twentieth century established that sequence dictates structure, framing folding as a self-assembly problem. From the late 1980s the discovery that heat-shock proteins and chaperonins assist folding in vivo reconciled this principle with the reality of the crowded cell, and the chaperone field expanded into the modern concept of proteostasis (Hartl et al., 2011; Balch et al., 2008).

Key figures

• Christian Anfinsen
• F. Ulrich Hartl
• Arthur Horwich
• Manajit Hayer-Hartl

Seminal works

• anfinsen-1973
• hartl-2002
• hartl-2011

Frequently asked questions

If the sequence determines the fold, why are chaperones needed?

The sequence still specifies the final structure, but in the crowded cell partly folded chains can stick together and aggregate before they fold. Chaperones prevent this and give the chain repeated chances to reach its native state; they do not change what that state is.

Are molecular chaperones the same as the proteins they help fold?

No. Chaperones are separate proteins that bind non-native chains transiently and are not part of the final folded product.