Two-dimensional infrared spectroscopy reveals an unexpected structure for amyloid fibers formed from human γD-crystallin, which is a major component of cataracts (Proc. Natl. Acad. Sci. USA, DOI: 10.1073/pnas.1117704109). Martin T. Zanni of the University of Wisconsin, Madison; Sean M. Decatur of Oberlin College; and coworkers found this structure through a method that extends isotope-edited 2-D IR spectroscopy to entire proteins. In the past, isotopic labeling on the amide carbonyl was performed on one amino acid at a time, and the method was limited to peptides that could be made by solid-phase synthesis. Now, the team uses 13C to label the amides in an entire segment of a protein and leave other segments unlabeled. They stitch the segments together to form the complete protein by using an existing method called expressed protein ligation. They used the 2-D IR method for structural studies of human γD-crystallin. Earlier work suggested that the β-sheets associated with amyloid fibrils formed in γD-crystallin’s N-terminal domain. This study of the complete protein instead suggests that fibril nucleation and growth occur in the C-terminal domain.