Chaperonin

A proportion of all newly-made proteins require assistance to convert from a linear chain of amino acids to a functional three-dimensional entity. This process is called protein folding. Chaperonins are protein complexes that assist the folding of these nascent, non-native polypeptides into their native, functional state. These proteins belong to a large class of molecules that assist protein folding, called molecular chaperones.

These molecular machines use chemical energy, in the form of Adenosine triphosphate (ATP), to promote protein folding in all cells.

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Structure

The structure of these chaperonins resemble two donuts stacked on top of one another to create a barrel.

Each ring is composed of either 7, 8 or 9 subunits depending on the organism in which the chaperonin is found.

Categories of Chaperonins

Group I

Group I chaperonins are found in prokaryotes as well as organelles of endosymbiotic origin: chloroplasts and mitochondria.

The GroEL/GroES complex in E. coli is a Group I chaperonin and the best characterized large (~ 1 MDa) chaperonin complex.

• GroEL is a double-ring 14mer with a greasy hydrophobic patch at its opening; it is so large it can accommodate native folding of 54-kDa GFP in its central cavity.
• GroES is a single-ring heptamer that binds to GroEL in the presence of ATP or transition state analogues of ATP hydrolysis, such as ADP-AlF₃. It's like a cover that covers GroEL (box/bottel).

GroEL/GroES may not be able to undo protein aggregates, but kinetically it competes in the pathway of misfolding and aggregation, thereby preventing aggregate formation.^[1]

Group II

Group II chaperonins, found in the eukaryotic cytosol and in archaebacteria, are more poorly characterized.

TRiC (TCP-1 Ring Complex, also called CCT), the eukaryotic chaperonin, is composed of eight different though related subunits, each thought to be represented once per eight-membered ring. TRiC was originally thought to fold only the cytoskeletal proteins actin and tubulin but is now known to fold dozens of substrates.

Mm cpn (Methanococcus maripaludis chaperonin), found in the archaea Methanococcus maripaludis, is composed of sixteen identical subunits (eight per ring). It has been shown to fold the mitochondrial protein rhodanese; however, no natural substrates have yet been identified.

Group II chaperonins are not thought to utilize a GroES-type cofactor to fold their substrates. They instead contain a "built-in" lid that closes in an ATP-dependent manner to encapsulate its substrates, a process that is required for optimal protein folding activity.

Mechanism of action

Chaperonins undergo large conformational changes during a folding reaction as a function of the enzymatic hydrolysis of ATP as well as binding of substrate proteins and cochaperonins, such as GroES. These conformational changes allow the chaperonin to bind an unfolded or misfolded protein, encapsulate that protein within one of the cavities formed by the two rings, and release the protein back into solution. Upon release, the substrate protein will either be folded or will require further rounds of folding, in which case it can again be bound by a chaperonin.

Conservation of structural and functional homology

As mentioned, all cells contain chaperonins.

• In bacteria, the archetype is the well-characterized chaperonin GroEL from E. coli.
• In archaea, the chaperonin is called the thermosome.
• In eukarya, the chaperonin is called CCT (also called TRiC or c-cpn).

These protein complexes appear to be essential for life in E. coli, Saccharomyces cerevisiae and higher eukaryotes. While there are differences between eukaryotic, bacterial and archaeal chaperonins the general structure and mechanism are conserved.

References

1. ^ "Chaperonin-mediated protein folding: fate of substrate polypeptide" Fenton and Horwich, Q Rev Biophys 36(2): 229-256, 2003. Entrez PubMed 14686103

See also

• Chaperone
• Heat shock protein