Within the living cell there are many very large proteins, yet they must be folded into very precise shapes or they will not function correctly. However, in the crowded environment of the cell, jostled by other compounds and objects, protein molecules would be hard pressed to fold correctly even occasionally. A review article on this topic tells us why this is so critical an issue. Incorrectly folded proteins can lead to serious human disease conditions for example such as neurodegeneration, type 2 diabetes, amyloidosis, cystic fibrosis, cancer and heart disease. To avoid this, quality control of protein folding and shape is achieved “by an integrated network of several hundred proteins, including most prominently, molecular chaperones and their regulators, which assist in de novo folding or refolding, and the ubiquitin-proteasome system (UPS) and autophagy system, which mediates the timely removal of irreversibly misfolded and aggregated proteins.” [F. Ulrich Hartl et al. 2011. Molecular chaperones in protein folding and proteostasis. Nature 475 PP. 324- 332].

Cells in all domains of life need elaborate chaperones to make sure that the proteins fold correctly. One of the most famous chaperon systems are the chaperonins, observed both in bacteria and eukaryotic cells. These molecular machines consist of a barrel-type structure with lids at each end. The unfolded protein chain enters the machine, the lid closes, and after it has folded in isolation, the protein exits at the opposite end of the barrel. Next a protein enters at that end, the lid closes, and after the protein folds, it exits at the opposite end.  The need for such folding assistance is particularly important for eukaryotic cells. Thus, the commentators tell us: “we are only beginning to appreciate the extent to which many proteins depend on macromolecular assistance throughout their cellular lifetime to maintain or regain functionally active conformations.” Apparently, the number of proteins in a eukaryotic cell is particularly problematic “comprising a much greater number and diversity of proteins … these proteins constantly face numerous challenges to their folded states.” [p. 329]

This situation raises a chicken-and-the egg issue. Which came first, the elaborate proteins necessary for the cell to function, or the complex protein machines required to fold these large proteins? Hartl et al. declare that the chaperones must have come early in cell evolution: “It seems likely, therefore, that the fundamental requirement for molecular chaperones arose very early during the evolution of densely crowded cells, owing to the need to minimize protein aggregation during folding and maintain proteins in soluble yet conformationally dynamic states.” [p. 324]

This system, that supposedly arose early in cell evolution, includes about 800 proteins involving about 200 chaperones and co-chaperones and about 600 UPS (waste disposal proteins) in human cells alone. [p. 329]. One has to be very credulous indeed to believe that such an elaborate system could arise spontaneously at the same time that most of the cell structure was supposedly developing! Obviously, these elaborately structured chaperones had to be present from the start. The more we learn about the living cell, the more apparent it becomes that God designed cells and whole organisms to function from the beginning.

Related Resources

On the evolution of chaperones and cochaperones and the expansion of proteomes across the Tree of Life Mathieu E. Rebeaud et al. 2021. Proceedings of the National Academy of Sciences. 118 pp. 1-10.