Descent of the Prion Protein Gene Family from the Extracellular Domain of an Ancestral Zip Metal Ion Transporter

Abstract

Since its discovery over twenty years ago, both the phylogenetic origin and the cellular function of the prion protein (PrP) have remained enigmatic. The subsequent discovery of the PrP paralog Doppel (Dpl) has strengthened the argument that the copper-binding ability of PrP and Dpl may be part of their cellular function.Chemical crosslinking provides insights into a possible function of PrP through the characterization of its molecular neighborhood on the cell surface. Quantitative interactome data demonstrated the spatial proximity of two putative zinc ion transporters of the ZIP family, ZIP6 (Slc39a6) and ZIP10 (Slc39a10), to mammalian prion proteins in vivo. A subsequent bioinformatic analysis revealed the unexpected presence of a PrP-like amino acid sequence within the N-terminal, extracellular domain of a distinct sub-branch of the ZIP protein family, which includes ZIP5, ZIP6 and ZIP10. Structural threading and orthologous sequence alignment analyses argue that the prion protein gene family is phylogenetically derived from a ZIP-like ancestral molecule. The level of sequence homology and the presence of prion protein genes in most chordate species place the split from the ZIP-like ancestor gene at the base of the chordate lineage. This relationship explains structural and functional features found within mammalian prion proteins as elements of an ancient involvement in the transmembrane transport of divalent cations, presumably zinc and/or copper. The phylogenetic and spatial connection to ZIP proteins is expected to open new and thus unexplored avenues of research to elucidate the biology of the prion protein in health and disease.