Describes how proteins fold and interact and how mis-folding can result in exponential accumulation of aggregates.
As mentioned proteins form the bulk of the cell and catalyze its chemical processes. Their production is its central activity of all cells..
Proteins are long single-chain polymers of small molecules called amino acids. 20 different types of amino acids are used to make proteins. The type and order of each amino acid in the protein chain strictly correspond to the type and order of nucleotide sequences in the cell’s DNA.
Of the 20 types of amino acids required for protein synthesis, the human body can make 11 from other substances. 9 types of amino acids however must be obtained from digestion of the proteins in the diet.
Protein chains are built up by adding one amino acid at a time. The chain so built then goes through a process called folding to assume the shape necessary to its function. Actually its more like a string wadding up into a ball. A protein is like a string of magnetic beads. The different segments of the string interact depending on the shape and charge of each bead (in this case each amino-acid) and the environment within which the folding occurs. Presumably segments of the string pair with other segments with high specificity like a three-dimensional jig-saw puzzle. This proceeds in the juvenile protein until the protein achieves the configuration suited to its function. Subsequent enzymatic modification to the juvenile protein may then further stabilize its final configuration.
Mis-folding can occur whenever anything goes wrong for whatever reason. It is thought that mis-folding of proteins may be involved in progressive neurodegenerative diseases like AD, PD, ALS and HD.
Mis-folded proteins may expose amino-acid sequences that are normally paired internally with other complementing sequences. A second protein molecule of the same type may then pair its complementing sequences with the exposed sequence of the mis-folded protein. Its now unpaired sequence may then trap a third instance of the protein and so on forming an aggregate in the cell that grows inexorably with time. In the final stages when the cell can no longer prevent oxidative damage, the aggregate may condense to form an insoluble indigestible condensate, the so-called inclusion body characteristic of these diseases. The aggregate may grow so large that it leaves no room for other vital cell functions. Or as the aggregate grows, more and more of the protein species of which it is composed may be unable to escape its expanding grasp. If that protein is needed elsewhere by the cell, its apparent deficiency could thereby weaken or kill the cell. Or the aggregate may trap the other protein species with which it normally interacts and make them unavailable.
While one molecule is folding another molecule of the same type can interact with it. This is possible because the other molecule also has the same complementary segments needed for precision pairing as the first. In the right circumstances this can result in the adult protein causing the juvenile protein also to mis-fold.
This interaction has been hypothesized as an explanation of how the prion diseases, scrapie, BSE and CJD, might operate. In these diseases, the infectious agent, the prion, is a protein. Presumably the mis-folded infecting protein interacts with the same or similar protein in the host and causes it to mis-fold. The newly mis-folded protein then persuades others of its kind to mis-fold in an exponential progression that, though slow, can ultimately mis-fold all instances of the protein.
Logically this might require that adult mis-folded protein be more likely than functional protein to combine with juvenile protein or that the mis-folded protein be degraded more slowly. Perhaps by consequence of having its pairing segments exposed, the mis-folded protein out-competes the functional in influencing juvenile folding . And perhaps by a tendency to aggregate, the mis-folded protein is protected from degradation.
This mis-folding cascade may be the slow but inexorable process in the prion diseases that can take decades to develop. The population of mis-folded protein doubles continually until there is enough to cause symptoms. Even if this involves hundreds of doublings, it is only the last that really matters where as much protein is mis-folded as in all the previous doublings combined. This is how the symptoms can suddenly appear decades after the initial infection event.
Perhaps this mis-folding cascade mechanism operates in some degree on other protein species, not just the prion-associated protein, and may account for some of the decline in cell vigor associated with aging and neurodegenerative diseases. If so, a mechanism to clear out aggregates would benefit cell longevity.