The ZIP5 Ectodomain Co-Localizes with PrP and May Acquire a PrP-Like Fold That Assembles into a Dimer

Pocanschi, Cosmin L.; Ehsani, Sepehr; Mehrabian, Mohadeseh; Wille, Holger; Reginold, William; Trimble, William S.; Wang, Hansen; Yee, Adelinda; Arrowsmith, C.H.; Bozóky, Zoltán; Kay, Lewis E.; Forman-Kay, Julie D.; Rini, James M.; Schmitt‐Ulms, Gerold

doi:10.1371/journal.pone.0072446

Cited by 22 publications

(26 citation statements)

References 43 publications

(63 reference statements)

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“…It is reported that SLC39A5 is situated in the Golgi membrane27 or cell membrane 28. However, our data showed that it is localised in the membrane of endoplasmic reticulum in HEK293 cells (see online supplementary figure S2–3).…”

Section: Resultsmentioning

confidence: 48%

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SLC39A5mutations interfering with the BMP/TGF-β pathway in non-syndromic high myopia

et al. 2014

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BackgroundHigh myopia, with the characteristic feature of refractive error, is one of the leading causes of blindness worldwide. It has a high heritability, but only a few causative genes have been identified and the pathogenesis is still unclear.MethodsWe used whole genome linkage and exome sequencing to identify the causative mutation in a non-syndromic high myopia family. Direct Sanger sequencing was used to screen the candidate gene in additional sporadic cases or probands. Immunofluorescence was used to evaluate the expression pattern of the candidate gene in the whole process of eye development. Real-time quantitative PCR and immunoblot was used to investigate the functional consequence of the disease-associated mutations.ResultsWe identified a nonsense mutation (c.141C>G:p.Y47*) in SLC39A5 co-segregating with the phenotype in a non-syndromic severe high myopia family. The same nonsense mutation (c.141C>G:p.Y47*) was detected in a sporadic case and a missense mutation (c.911T>C:p.M304T) was identified and co-segregated in another family by screening additional cases. Both disease-associated mutations were not found in 1276 control individuals. SLC39A5 was abundantly expressed in the sclera and retina across different stages of eye development. Furthermore, we found that wild-type, but not disease-associated SLC39A5 inhibited the expression of Smadl, a key phosphate protein in the downstream of the BMP/TGF-β (bone morphogenic protein/transforming growth factor-β) pathway.ConclusionsOur study reveals that loss-of-function mutations of SLC39A5 are associated with the autosome dominant non-syndromic high myopia, and interference with the BMP/TGF-β pathway may be one of the molecular mechanisms for high myopia.

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Section: Resultsmentioning

confidence: 48%

“…We revealed that this variant, as with Y47*, lost the function to suppress Smad1 expression. SLC39A5 has been reported suiting in Golgi27 or plasma membrane 28. However, we revealed that SLC39A5 is localised in the membrane of the endoplasmic reticulum in HEK293 cells.…”

Section: Discussionmentioning

confidence: 51%

SLC39A5mutations interfering with the BMP/TGF-β pathway in non-syndromic high myopia

et al. 2014

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“…Moreover, processing is likely to be important for regulating their cellular trafficking (159). Intriguingly, an evolutionary link has been proposed in the extracellular portion between some LIV-1 subfamily transporters (ZIP5, ZIP6, and ZIP10) and the prion proteins, in which the PrPlike amino acid sequence is found (89,90,324,363). These results suggest that particular ZIP transporters may be involved in the etiology of prion diseases.…”

Section: B Zip Transportersmentioning

confidence: 95%

“…IIIB). Intriguingly, ZIP5 can be colocalized with the cellular prion protein (PrP C ) at the plasma membrane and in Rab5 immunoreactive endosomes in neuroblastoma cells (324).…”

Section: E Zip5 (Liv-1 Subfamily)mentioning

confidence: 99%

The Physiological, Biochemical, and Molecular Roles of Zinc Transporters in Zinc Homeostasis and Metabolism

Kambe

Tsuji

Hashimoto

et al. 2015

Physiological Reviews

856

797

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Zinc is involved in a variety of biological processes, as a structural, catalytic, and intracellular and intercellular signaling component. Thus zinc homeostasis is tightly controlled at the whole body, tissue, cellular, and subcellular levels by a number of proteins, with zinc transporters being particularly important. In metazoan, two zinc transporter families, Zn transporters (ZnT) and Zrt-, Irt-related proteins (ZIP) function in zinc mobilization of influx, efflux, and compartmentalization/ sequestration across biological membranes. During the last two decades, significant progress has been made in understanding the molecular properties, expression, regulation, and cellular and physiological roles of ZnT and ZIP transporters, which underpin the multifarious functions of zinc. Moreover, growing evidence indicates that malfunctioning zinc homeostasis due to zinc transporter dysfunction results in the onset and progression of a variety of diseases. This review summarizes current progress in our understanding of each ZnT and ZIP transporter from the perspective of zinc physiology and pathogenesis, discussing challenging issues in their structure and zinc transport mechanisms.

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“…Taylor et al reported that ZIP6 and ZIP10 form heteromers similar to PrP structures and influences cell migration [37]. PrP C colocalizes with ZIP5 and forms dimers [38]. These findings strongly suggest that PrP [39].…”

Section: Zn and Normal Prion Proteinmentioning

confidence: 91%

Disruption of Metal Homeostasis and the Pathogenesis of Prion Diseases

Kawahara¹,

Tanaka²,

Mizuno³

2017

Prion - An Overview

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Prion diseases are progressive neurodegenerative diseases that are associated with the conformational conversion of normal cellular prion protein (PrP C ) into abnormal pathogenic prion protein (PrP Sc ). PrP C is a metal-binding protein that is located in the synapse and possesses the ability to bind to various metals, including Cu, Zn, Mn and Fe. Moreover, increasing evidence suggests that PrP C plays essential roles in the maintenance of metal homeostasis in the synapse. Trace elements have a crucial influence on the conformational change of PrP C . Given that other disease-related proteins such as β-amyloid protein and its precursor protein (APP) in Alzheimer's disease also exist in the synapse and possess a metal-binding ability, an interaction between PrP and metals and between PrP and APP, may occur in the synapse; the resulting metal homeostasis may lead to the pathogenesis of prion diseases. Here, we review our studies and other new findings that inform the current understanding of the link between trace elements and physiological functions of PrP C and the neurotoxicity of PrP Sc .

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The ZIP5 Ectodomain Co-Localizes with PrP and May Acquire a PrP-Like Fold That Assembles into a Dimer

Cited by 22 publications

References 43 publications

SLC39A5mutations interfering with the BMP/TGF-β pathway in non-syndromic high myopia

SLC39A5mutations interfering with the BMP/TGF-β pathway in non-syndromic high myopia

The Physiological, Biochemical, and Molecular Roles of Zinc Transporters in Zinc Homeostasis and Metabolism

Disruption of Metal Homeostasis and the Pathogenesis of Prion Diseases

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