Huntington’s disease, a lethal neurodegenerative condition, is believed to be caused by misfolding of mutated versions of huntingtin protein in which a glutamine-containing sequence is repeated too many times. But how the protein misfolds is still uncertain. Researchers have speculated that the conformation of monomeric huntingtin undergoes a sharp transition when the number of glutamine repeats exceeds 36 or 37, making the domain inflexible, like a rusty hinge. However, mutant huntingtin monomers have been difficult to study because they aggregate rapidly. Hilal A. Lashuel of the Swiss Federal Institute of Technology, Lausanne (EPFL), Rohit V. Pappu of Washington University in St. Louis, Edward A. Lemke of the European Molecular Biology Laboratory, and coworkers have now used protein semisynthesis, single-molecule fluorescence resonance energy transfer spectroscopy, and atomistic computer simulations to structurally characterize huntingtin monomers (J. Am. Chem. Soc. 2017, DOI: 10.1021/jacs.7b06659). The study reveals that the monomers have a tadpolelike structure with a globular head and flexible tail. Glutamine repeats are in the head, which enlarges gradually as the repeat number increases instead of being part of a sharp structural transition. The researchers propose that this enlargement, rather than a rusty hinge, may cause misfolding.