캐나다 토론토 대학 제럴드 슈미트 울름스(Gerold Schmitt-Ulms) 교수가 이끄는 연합연구팀이 프리온 단백질 유전자의 진화상 기원을 규명한 연구결과를 9월 28일자 [PLoS ONE]에 발표했습니다.
연구팀에 따르면, 프리온 유전자는 금속 이온 운반자(metal ion transporters)인 고대 ZIP 단백질들로부터 진화해온 것으로 밝혀졌습니다. ZIP 계열 단백질들은 아연을 비롯한 다른 금속 이온들을 세포막을 통과하도록 운반하는 기능을 하고 있는 것으로 잘 알려져 있습니다. 프리온 유전자는 생체내 아연 운반 단백질인 ZIP6 및 ZIP10과 물리적으로 유사하며, 프리온 유전자의 N 터미날의 아미노산 시퀀스에는 ZIP5, ZIP6, ZIP10을 포함하는 ZIP 계열 단백질들과의 유사성이 확인되었습니다.
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Evolutionary Descent of Prion Genes from the ZIP Family of Metal Ion Transporters
1 Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada, 2 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada, 3 Institute for Neurodegenerative Diseases, University of California San Francisco, San Francisco, California, United States of America, 4 Department of Neurology, University of California San Francisco, San Francisco, California, United States of America, 5 Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta, Canada
출처 : http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0007208(전문은 첨부파일 참조)
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.
Citation: Schmitt-Ulms G, Ehsani S, Watts JC, Westaway D, Wille H (2009) Evolutionary Descent of Prion Genes from the ZIP Family of Metal Ion Transporters. PLoS ONE 4(9): e7208. doi:10.1371/journal.pone.0007208
Editor: Art F. Y. Poon, University of California San Diego, United States of America
Received: June 16, 2009; Accepted: August 25, 2009; Published: September 28, 2009
Copyright: © 2009 Schmitt-Ulms et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: Work on this project was funded through support from the Canadian Institutes of Health Research (MOP-74734-GSU and MOP36377-DW), a fellowship to J.C.W. from the Natural Sciences and Engineering Research Council of Canada (PGSD2-319161-2005), the Alberta Heritage Foundation for Medical Research (Grant 200600752) and the National Institutes of Health (NIH AG02132 and AG10770). G.S.-U. received support from the W. Garfield Weston Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
* E-mail: g.schmittulms@utoronto.ca
Evolutionary Origins Of Prion Disease Gene Uncovered
출처 : ScienceDaily (Sep. 29, 2009)
http://www.sciencedaily.com/releases/2009/09/090928131210.htm
— A University of Toronto-led team has uncovered the evolutionary ancestry of the prion gene, which may reveal new understandings of how the prion protein causes diseases such as bovine spongiform encephalopathy (BSE), also known as “mad cow disease.”
Diseased prion proteins are responsible for the fatal neurodegenerative Creutzfeldt-Jakob disease (CJD) in humans, and BSE, scrapie and chronic wasting disease (CWD) in livestock. Overall, this work holds promise for efforts to reveal the physiological function of members of the prion protein family and may provide insights into the origins and underlying constraints of the conformational changes associated with prion diseases. The study was published on September 28, 2009, in the online journal PLoS ONE.
Principal investigator Gerold Schmitt-Ulms (Centre for Research in Neurodegenerative Diseases; Department of Laboratory Medicine and Pathobiology, U of T) and his graduate student Sepehr Ehsani teamed up with Holger Wille and Joel Watts (University of California, San Francisco) and David Westaway (University of Alberta) for this project. “The prion protein was discovered over twenty years ago and has been studied intensively. Nobody, however, knew its evolutionary origin and much confusion surrounds its physiological function,” says Prof. Schmitt-Ulms. The team’s analysis suggests that the prion gene is descended from the more ancient ZIP family of metal ion transporters. Members of the ZIP protein family are well known for their ability to transport zinc and other metals across cell membranes.
The U of T laboratory initially demonstrated the physical proximity of two metal ion transporters, ZIP6 and ZIP10, to mammalian prion proteins in living cells. As with the normal cellular prion protein, ZIP6 and ZIP10 exhibit widespread expression in biological tissues with high transcript levels in the brain. Schmitt-Ulms then made the startling discovery that prion and ZIP proteins contain extensive stretches of similar amino acid sequence. The researchers next documented that the respective segments within ZIP and prion proteins are computationally predicted to acquire a highly similar three-dimensional structure. Finally, the team uncovered multiple additional commonalities between ZIP and prion proteins which led them to conclude these molecules are evolutionarily related.
Most proteins do not act in isolation but partner with other proteins to exert their biological roles. The relationship between ZIP-family and prion proteins may thus provide a new angle from which to study the biology of the prion protein in health and disease. The level of shared characteristics between these protein families, in addition to the presence of prion protein genes in most chordate (i.e., backboned) species, place the split from the ZIP-like ancestor gene at the base of the chordate lineage.
Although no single evidence firmly established the phylogenetic relationship between ZIP and prion genes, Schmitt-Ulms is confident that the many corroborating pieces of evidence collected and, equally important, the absence of any conflicting observations, allow no other conclusion to be drawn.
This project was funded with support from the Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, Alberta Heritage Foundation for Medical Research, National Institutes of Health and W. Garfield Weston Foundation.
Journal reference:
- Gerold Schmitt-Ulms, Sepehr Ehsani, Joel C. Watts, David Westaway, Holger Wille. Evolutionary Descent of Prion Genes from the ZIP Family of Metal Ion Transporters. PLoS ONE, September 28, 2009 DOI: 10.1371/journal.pone.0007208
