Imagine linking together a chain of 300 plastic shapes, some with magnets at various places. Then let it go and see if you could get it to fold spontaneously into a teapot. This is the challenge that cells face every minute: folding long chains of amino acids (polypeptides) into molecular machines and structures for the cell’s numerous tasks required for life. DNA in the nucleus codes for these polypeptides. They are assembled in ribosomes in single-file order. How do they end up in complex folded shapes? Some polypeptides will spontaneously collapse into their native folds, like the magnetic chain in our analogy. Others, however, need help. Fortunately, the cell provides an army of assistants, called chaperones, to monitor, coax, and repair unfolded proteins, to achieve “proteostasis” – a stable, working set of proteins. That army is so well-organized and complex, scientists continue to try to figure out how it performs so well in the field.
Polypeptide chains don’t have magnets, but they have amino acids that produce other forces: side chains that are hydrophilic (water-loving) or hydrophobic (water-repelling), side chains that are acidic or basic, and side chains that are attracted chemically to certain other amino acids. Let some of these chains go in a test tube and they will spontaneously fold properly because of the precise way they were coded by DNA. Others require the help of chaperones to fold. In a review article last week in Nature,1Hartl, Bracher and Hayer-Hartl from the Max Planck Institute surveyed what is currently known about protein chaperones. The importance of proteostasis is evident in their first paragraph:
Most proteins must fold into defined three-dimensional structuresto gain functional activity. But in the cellular environment, newly synthesized proteins are at great risk of aberrant folding and aggregation, potentially forming toxic species. To avoid these dangers, cells invest in a complex network of molecular chaperones, which use ingenious mechanisms to prevent aggregation and promote efficient folding. Because protein molecules are highly dynamic, constant chaperone surveillance is required to ensure protein homeostasis (proteostasis). Recent advances suggest that an age-related decline in proteostasis capacity allows the manifestation of various protein-aggregation diseases, including Alzheimer’s disease and Parkinson’s disease. Interventions in these and numerous other pathological states may spring from a detailed understanding of the pathways underlying proteome maintenance.
Our mammalian cells typically assemble 10,000 different types of proteins. How they fold properly is “one of the most fundamental and medically relevant problems in biology,” the authors said. The folded states, furthermore, must be loose enough in many cases to allow for movements (conformational changes) that are essential to their functions….
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