Abstract
The cellular prion protein, notorious for its causative role in a range of fatal neurodegenerative diseases, evolved from a Zrt-/Irt-like Protein (ZIP) zinc transporter approximately 500 million years ago. Whilst atomic structures for recombinant prion protein (PrP) from various species have been available for some time, and are believed to stand for the structure of PrPC, the first structure of a ZIP zinc transporter ectodomain was reported only recently. Here, we compare this ectodomain structure to structures of recombinant PrP. A shared feature of both is a membrane-adjacent helix-turn-helix fold that is coded by a separate exon in the respective ZIP transporters and is stabilized by a disulfide bridge. A ‘CPALL’ amino acid motif within this cysteine-flanked core domain appears to be critical for dimerization and has undergone stepwise regression in fish and mammalian prion proteins. These insights are intriguing in the context of repeated observations of PrP dimers. Other structural elements of ZIP transporters and PrP are discussed with a view to distilling shared versus divergent biological functions.
Highlights
Prion proteins are notorious for their central role in fatal neurodegenerative diseases in a subset of mammalian species, including humans [1,2,3]
A regression of this extended CPALL motif appears to have occurred throughout PrP evolution, i.e., fish prion proteins lack the cysteine residue, which is present in its closest Zrt-/Irt-like Protein (ZIP) relatives, and a full replacement of the PAL motif with a sequence stretch characterized by polar amino acids occurred in mammalian PrP genes (Figure 2B)
PrP relative, there are limits to the extent insights into its biology will be informative for understanding
Summary
Prion proteins are notorious for their central role in fatal neurodegenerative diseases in a subset of mammalian species, including humans [1,2,3]. High-resolution structural data were only available for recombinantly expressed PrP [27,28,29], but not for ZIPs. What are the structural features that govern these similarities and differences between PrP and its closest ZIP family members? The ZIP ectodomain structure is from ZIP4, a relatively distant PrP relative [10], the sequence of its membrane-adjacent domain is sufficiently similar to ZIP6 and ZIP10 to be of interest in this context We describe this structure, compare it to PrP, and discuss its significance for understanding the biology and evolution of mammalian prion proteins.
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