Abstract
In the more than twenty years since its discovery, both the phylogenetic origin and cellular function of the prion protein (PrP) have remained enigmatic. Insights into a possible function of PrP may be obtained through the characterization of its molecular neighborhood in cells. Quantitative interactome data demonstrated the spatial proximity of two metal ion transporters of the ZIP family, ZIP6 and ZIP10, 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 that includes ZIP5, ZIP6 and ZIP10. Additional structural threading and orthologous sequence alignment analyses argued that the prion 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. The phylogenetic and spatial connection to ZIP proteins is expected to open new avenues of research to elucidate the biology of the prion protein in health and disease.
Highlights
Prion diseases are fatal neurodegenerative diseases of humans and animals which, in addition to sporadic and familial modes of manifestation, can be acquired via an infectious route of propagation
Cells were stably transfected with expression plasmids coding for individual members of the mammalian prion protein family that had been FLAG-tagged in the vicinity of the Nterminus of the mature protein or with a negative control vector [15]
A comprehensive analysis of samples led to the identification of approximately one hundred proteins, more than thirty of which were observed with isobaric tags for relative and absolute quantitation (iTRAQ) signature mass intensity ratios that suggested specific co-enrichment with members of the prion protein family (Figure S1, Watts, J.C., et al, in revision)
Summary
Prion diseases are fatal neurodegenerative diseases of humans and animals which, in addition to sporadic and familial modes of manifestation, can be acquired via an infectious route of propagation. Prion diseases include sporadic and variant forms of Creutzfeldt-Jakob disease in humans. The function of a protein can sometimes be inferred from genomic investigations which may reveal proteins with similar sequences or sequence modules of known function. Extensive investigations of this kind have provided evidence for PrP-related sequences in most species of the vertebrate lineage [4,5,6] and revealed two mammalian paralog sequences encoding for the proteins Doppel (Dpl) and Shadoo (Sho), which together with
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