The final step in information flow from DNA to mature protein involves the proper folding of the newly synthesized polypeptide into its biologically active form. Although the blueprint for a protein’s three-dimensional shape is encoded in its amino acid sequence, a group of proteins called molecular chaperones often provides assistance during the folding process.
Art Horwich has spent much of his career investigating a ring-shaped chaperone called a chaperonin. Using a variety of methods, Horwich and his colleagues have captured snapshots of this protein-folding machine in action. By combining these static images with biochemical tests, the scientists were able to piece together the details of how the cylindrical chaperonin does its job. First, it binds an unfolded protein in a ring via a “greasy” surface, which eventually becomes buried in the folded state. This binding step prevents protein misfolding and aggregation. Second, a co-chaperonin “lid” caps the open end of the ring, encapsulating the unfolded protein, and allows it to fold in solitary confinement, without the possibility of aggregation. After 10 seconds, the lid pops off and the properly folded protein emerges.
Recently, Horwich’s team turned their attention to amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease), a disease often caused by mutations in an enzyme called superoxide dismutase 1 (SOD1). Unable to fold correctly, the mutant protein forms toxic aggregates that disable motor neurons that extend down the body’s limbs and operate the muscles. Horwich and his colleagues have created a transgenic mouse model for ALS and are using it to understand how mutant SOD1 causes neuronal damage and malfunction. They’ve observed that fast-firing motor neurons are most susceptible to cell death. In parallel studies, they have overproduced in neurons of the ALS mice a chaperone, heat-shock protein 110 (Hsp110), that has recently been recognized to function as a rate-limiting component in a disaggregase chaperone complex in the mammalian cytosol. Overproduction of Hsp110 in motor neurons extended the median lifespan of the ALS mice by 30%, and the longest-lived mice lived twice as long.
Grants from the National Institutes of Health supported a portion of this work.