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Pathogens 2018, 7(1), 4; https://doi.org/10.3390/pathogens7010004

The Evolutionary unZIPping of a Dimerization Motif—A Comparison of ZIP and PrP Architectures

1
Department of Chemistry, Michigan State University, East Lansing, MI 48824, USA
2
Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA
3
Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2M8, Canada
4
Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB T6G 2M8, Canada
5
Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON M5T 2S8, Canada
6
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada
*
Author to whom correspondence should be addressed.
Received: 5 December 2017 / Revised: 20 December 2017 / Accepted: 22 December 2017 / Published: 29 December 2017
(This article belongs to the Special Issue PrPSc prions: state of the art)
Full-Text   |   PDF [1371 KB, uploaded 29 December 2017]   |  

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. View Full-Text
Keywords: ZIP metal ion transporter; prion protein; dimerization; evolution ZIP metal ion transporter; prion protein; dimerization; evolution
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Hu, J.; Wille, H.; Schmitt-Ulms, G. The Evolutionary unZIPping of a Dimerization Motif—A Comparison of ZIP and PrP Architectures. Pathogens 2018, 7, 4.

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