Protein Misfolding: Origami Medicine
Denise Bosco for Proto
Many genetic disorders stem from mutations in DNA that produce a protein with a slightly different sequence of amino acids than normal, which causes the protein to misfold. In one main category of these illnesses—loss-of-function diseases such as cystic fibrosis, Gaucher’s disease and related lysosomal storage diseases—the errant protein is targeted for early destruction and is never able to do its job (exactly how this happens differs from one disease to another and in some cases isn’t fully understood). That’s more or less the opposite of what occurs with a second big classification of folding disorders: gain-of-function diseases, which include Huntington’s, Alzheimer’s, type 2 diabetes and a group of illnesses called familial amyloidoses. In this case, instead of being destroyed, a misfolded protein breaks down and is put back together in an aggregate form that causes toxic damage—it does things that were never intended to occur (here, too, specific mechanisms are still being studied).
The symptoms of a particular disease depend on the type of tissue that holds the misfolded protein. In the most common mutation that causes cystic fibrosis, ΔF508, a protein called the cystic fibrosis transmembrane regulator, or CFTR, misfolds and is destroyed, and the lack of CFTR causes thick, sticky mucus, which builds up in the lungs and the pancreas. In Huntington’s disease, the misfolded huntingtin protein breaks down, then re-forms into an aggregate in the brain that causes neurological damage. In TTR amyloid polyneuropathy, the liver makes the protein TTR, which misfolds and ends up in peripheral nerve tissue as the aggregate TTR amyloid, which results in loss of sensation, muscle weakness and autonomic nerve problems that may affect the gastrointestinal and urinary tracts, among other systems.
During protein folding, ribosomes—small cellular structures in the cytoplasm—translate genetic information into long strings of amino acids known as polypeptides. From these chains, the protein folds itself into an intermediate structure and then into its final three-dimensional form. Proteins constantly fold and refold as they interact with other proteins and enzymes. And although many of the ins and outs remain poorly understood, research has shone light on the roles of chaperones and signaling pathways, which moderate this dynamic process. Chaperones are molecules that promote proper folding by binding to misfolded or aggregated proteins and providing a second chance for them to fold correctly. For their part, signaling pathways respond to cues from the environment to regulate not just how proteins fold but also how they’re made, moved, aggregated and degraded.
One of the best understood pathways is the heat shock response. Richard Morimoto, a professor of molecular biology at Northwestern University, began working with heat shock genes more than 30 years ago, just after their discovery, and he and other researchers found that cells have a molecular thermometer that can turn genes on and off—thus increasing or decreasing production of the proteins associated with those genes. When a cell’s temperature was raised, the cell began to synthesize great numbers of heat shock proteins, or HSPs. This same pathway turns out to exist in all organisms, from yeast to humans. A substance called heat shock factor, or HSF, controls the response.