The downstream prion-like protein (doppel, or Dpl) is a paralog of the cellular prion protein, PrP C . The two proteins have Ϸ25% sequence identity, but seem to have distinct physiologic roles. Unlike PrP C , Dpl does not support prion replication; instead, overexpression of Dpl in the brain seems to cause a completely different neurodegenerative disease. We report the solution structure of a fragment of recombinant mouse Dpl (residues 26 -157) containing a globular domain with three helices and a small amount of -structure. Overall, the topology of Dpl is very similar to that of PrP C . Significant differences include a marked kink in one of the helices in Dpl, and a different orientation of the two short -strands. Although the two proteins most likely arose through duplication of a single ancestral gene, the relationship is now so distant that only the structures retain similarity; the functions have diversified along with the sequence.doppel protein structure ͉ NMR ͉ protein structures ͉ prion protein ͉ prion diseases