A domain-swapped RNase A dimer with implications for amyloid formation

Bovine pancreatic ribonuclease (RNase A) forms two types of dimers (a major and a minor component) upon concentration in mild acid. These two dimers e xhibit different biophysical and biochemical properties. Earlier we reporte d that the minor dimer forms by swapping its N-terminal. alpha -helix with that of an identical molecule. Here we find that the major dimer forms by s wapping its C-terminal beta -strand, thus revealing the first example of th ree-dimensional (3D) domain swapping taking place in different parts of the same protein. This feature permits RNase A to form tightly bonded higher o ligomers. The hinge loop of the major dimer, connecting the swapped beta -s trand to the protein core, resembles a short segment of the polar zipper pr oposed by Perutz and suggests a model for aggregate formation by 3D domain swapping with a polar zipper.