Chaparonins in human cells rehabilitate misfolded proteins by capturing them in confined spaces causing them to unfold, giving them a second chance at refolding into their properly functioning, three-dimensional configuration.

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Proteins perform the vast majority of biochemical "jobs" necessary for the cell's survival, growth, reproduction, communication, etc. – correct functionality is dependent on each protein's very precise three-dimensionally folded structure called the "native" state. Newly synthesized proteins self-assemble into their native state based on the interaction of different parts of these large molecules. Oppositely charged areas move towards each other, while similarly charged areas repel; polar areas migrate towards the watery exterior, while hydrophobic areas aggregate towards the interior. Short range van der Waals forces and hydrogen bonds also contribute to forming the spirals, sheets, and pleats that characterize a properly folded protein molecule. But sometimes, the folding process goes awry resulting in a misfolded protein that at best is a waste of cellular resources, or at worse, a cause of disease. Chaparonins are cellular devices that relax misfolded proteins giving them a second chance at proper folding.

Chaperonins: Sometimes ribosomes (A) stitch together amino acids into useless forms (B). These can be taken up by the chaperonins (C), which unravel the useless forms and put them back out into the cell to be assembled into the useful native protein state (E). Artist: Emily Harrington. Copyright: All rights reserved. See gallery for details.

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"[P]roteins are able to rapidly and efficiently reach the native state. This is the result of actions by a collective of cellular machines, known as molecular chaperones, that provide kinetic assistance to the folding process, keeping proteins out of kinetic traps and effectively serving to 'smooth' the energy landscape. Studies of the past 15 years indicate that molecular chaperones function as a class by specifically binding non-native [misfolded] states of proteins through exposed hydrophobic surfaces that eventually become buried to the interior in the native state, effectively forestalling aggregation (e.g. Bukau & Horwich, 1998; Hartl & Hayer-Hartl, 2002). Bound proteins are then released, in many cases via the action of ATP, for another attempt at folding. In some cases, a net change of protein conformation attends the step of binding and/or release, whereas in others there is no observable change, but the overall action is rather one of protecting the protein from misfolding and aggregation until it can successfully proceed to a next step of biogenesis." (Fenton and Horwich 2003: 230)

Journal article
Chaperonin-mediated protein folding: fate of substrate polypeptideQuarterly Reviews of BiophysicsOctober 24, 2003
Wayne A. Fenton, Arthur L. Horwich

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