Design of three-dimensional domain-swapped dimers and fibrous oligomers

Three-dimensional (3D) domain-swapped proteins are intermolecularly folded analogs of monomeric proteins; both are stabilized by the identical interac tions, but the individual domains interact intramolecularly in monomeric pr oteins, whereas they form intermolecular interactions in 3D domain-swapped structures. The structures and conditions of formation of several domain-sw apped dimers and trimers are known, but the formation of higher order 3D do main-swapped oligomers has been less thoroughly studied. Here we contrast t he structural consequences of domain swapping from two designed three-helix bundles: one with an up-down-up topology, and the other with an up-down-do wn topology. The up-down-up topology gives rise to a domain-swapped dimer w hose structure has been determined to 1.5 Angstrom resolution by x-ray crys tallography. In contrast, the domain-swapped protein with an up-down-down t opology forms fibrils as shown by electron microscopy and dynamic light sca ttering. This demonstrates that design principles can predict the oligomeri c state of 3D domain-swapped molecules, which should aid in the design of d omain-swapped proteins and biomaterials.