Huntingtin’s spherical solenoid structure enables polyglutamine tract-dependent modulation of its structure and function

Huntington’s disease is an inherited disorder that occurs in adulthood and sometimes in children. It causes progressive damage to the brain and people with the condition develop memory loss, movement difficulties, confusion, and other symptoms of mental decline. Eventually, the disease leads to death. Mutations in the gene that encodes a protein called huntingtin cause Huntington’s disease. Individuals who inherit just one copy of the mutated gene develop the condition. No treatments currently exist that can slow or stop disease progression. Genetic and molecular studies are beginning to shed light on how mutations in the gene encoding huntingtin cause the disease. Normally, the protein has a section near its tail end made up of the amino acid glutamine repeated around 23 times. Mutations that increase the number of glutamines to more than 38 cause Huntington’s disease. The more extra glutamines there are in this region of the protein, the earlier in life the disease symptoms begin. But it was not clear how these extra glutamines near the tail of huntingtin affect the structure and behavior of a protein that is more than 3,000 amino acids long. Now, Vijayvargia et al. have revealed why the tail end of huntingtin is so important. Several biophysical methods were used to determine the three-dimensional structure of the huntingtin protein. These methods revealed that the protein folds up into a hollow sphere and that its tail end is able to interact with the entire length of the protein and physically touches its opposite end. To see this in more detail, Vijayvargia et al. used another experimental technique called crosslinking mass spectrometry to confirm which parts of the huntingtin protein are in close contact with each other. Together with the structural data, these experiments suggest that the stretch of glutamines is in the position to bring about subtle, but widespread, changes throughout the huntingtin protein. That is to say, that having more glutamines slightly changes the curve of the sphere and alters the way different parts of the protein interact. Together the new findings explain why mutations that alter the tail of huntingtin affect the rest of the protein. Further work will now aim to provide a more-detailed structure of the huntingtin protein and to investigate what other roles of huntingtin are affected by the increased number of glutamines in the protein’s tail. These insights may help scientists understand how the mutated protein causes brain decline.