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  • 1. Arioz, Candan
    et al.
    Li, Yaozong
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Wittung-Stafshede, Pernilla
    The six metal binding domains in human copper transporter, ATP7B: molecular biophysics and disease-causing mutations2017Ingår i: Biometals, ISSN 0966-0844, E-ISSN 1572-8773, Vol. 30, nr 6, s. 823-840Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Wilson Disease (WD) is a hereditary genetic disorder, which coincides with a dysfunctional copper (Cu) metabolism caused by mutations in ATP7B, a membrane-bound P-1B-type ATPase responsible for Cu export from hepatic cells. The N-terminal part (similar to 600 residues) of the multi-domain 1400-residue ATP7B constitutes six metal binding domains (MBDs), each of which can bind a copper ion, interact with other ATP7B domains as well as with different proteins. Although the ATP7B's MBDs have been investigated in vitro and in vivo intensively, it remains unclear how these domains modulate overall structure, dynamics, stability and function of ATP7B. The presence of six MBDs is unique to mammalian ATP7B homologs, and many WD causing missense mutations are found in these domains. Here, we have summarized previously reported in vitro biophysical data on the MBDs of ATP7B and WD point mutations located in these domains. Besides the demonstration of where the research field stands today, this review showcasts the need for further biophysical investigation about the roles of MBDs in ATP7B function. Molecular mechanisms of ATP7B are important not only in the development of new WD treatment but also for other aspects of human physiology where Cu transport plays a role.

  • 2. Hu, Yunping
    et al.
    Jin, Taiyi
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Miljömedicin.
    Zhou, Tong
    Pang, Bing
    Wang, Yunfei
    Effects of zinc on gene expressions induced by cadmium in prostate and testes of rats2004Ingår i: Biometals, ISSN 0966-0844, E-ISSN 1572-8773, Vol. 17, nr 5, s. 571-572Artikel i tidskrift (Refereegranskat)
  • 3. Kumar, Ranjeet
    et al.
    Arioz, Candan
    Li, Yaozong
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Bosaeus, Niklas
    Rocha, Sandra
    Wittung-Stafshede, Pernilla
    Disease-causing point-mutations in metal-binding domains of Wilson disease protein decrease stability and increase structural dynamics2017Ingår i: Biometals, ISSN 0966-0844, E-ISSN 1572-8773, Vol. 30, nr 1, s. 27-35Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    After cellular uptake, Copper (Cu) ions are transferred from the chaperone Atox1 to the Wilson disease protein (ATP7B) for incorporation into Cu-dependent enzymes in the secretory pathway. Human ATP7B is a large multi-domain membrane-spanning protein which, in contrast to homologues in other organisms, has six similar cytoplasmic metal-binding domains (MBDs). The reason for multiple MBDs is proposed to be indirect modulation of enzymatic activity and it is thus intriguing that point mutations in MBDs can promote Wilson disease. We here investigated, in vitro and in silico, the biophysical consequences of clinically-observed Wilson disease mutations, G85V in MBD1 and G591D in MBD6, incorporated in domain 4. Because G85 and G591 correspond to a conserved Gly found in all MBDs, we introduced the mutations in the well-characterized MBD4. We found the mutations to dramatically reduce the MBD4 thermal stability, shifting the midpoint temperature of unfolding by more than 20 A degrees C. In contrast to wild type MBD4 and MBD4D, MBD4V adopted a misfolded structure with a large beta-sheet content at high temperatures. Molecular dynamic simulations demonstrated that the mutations increased backbone fluctuations that extended throughout the domain. Our findings imply that reduced stability and enhanced dynamics of MBD1 or MBD6 is the origin of ATP7B dysfunction in Wilson disease patients with the G85V or G591D mutation.

  • 4.
    Lagerkvist, Birgitta Json
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Yrkes- och miljömedicin.
    Lundström, Nils-Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Yrkes- och miljömedicin.
    Lead- and cadmium levels in children living close to a copper and lead smelter in Sweden2004Ingår i: Biometals, ISSN 0966-0844, E-ISSN 1572-8773, Vol. 17, nr 5, s. 593-594Artikel i tidskrift (Övrigt vetenskapligt)
  • 5.
    Petzoldt, Svenja
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Center of Life and Food Sciences, Technische Universität München, Freising, Germany.
    Kahra, Dana
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Kovermann, Michael
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Dingeldein, Artur PG
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Niemiec, Moritz S.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Ådén, Jörgen
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Wittung-Stafshede, Pernilla
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Human cytoplasmic copper chaperones Atox1 and CCS exchange copper ions in vitro2015Ingår i: Biometals, ISSN 0966-0844, E-ISSN 1572-8773, Vol. 28, nr 3, s. 577-585Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    After Ctr1-mediated copper ion (Cu) entry into the human cytoplasm, chaperones Atox1 and CCS deliver Cu to P-1B-type ATPases and to superoxide dismutase, respectively, via direct protein-protein interactions. Although the two Cu chaperones are presumed to work along independent pathways, we here assessed cross-reactivity between Atox1 and the first domain of CCS (CCS1) using biochemical and biophysical methods in vitro. By NMR we show that CCS1 is monomeric although it elutes differently from Atox1 in size exclusion chromatography (SEC). This property allows separation of Atox1 and CCS1 by SEC and, combined with the 254/280 nm ratio as an indicator of Cu loading, we demonstrate that Cu can be transferred from one protein to the other. Cu exchange also occurs with full-length CCS and, as expected, the interaction involves the metal binding sites since mutation of Cu-binding cysteine in Atox1 eliminates Cu transfer from CCS1. Cross-reactivity between CCS and Atox1 may aid in regulation of Cu distribution in the cytoplasm.

  • 6. Shanmugavel, Kumaravel Ponnandai
    et al.
    Kumar, Ranjeet
    Li, Yaozong
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Department of Biochemistry, University of Zurich, 8006 Zurich, Switzerland.
    Wittung-Stafshede, Pernilla
    Wilson disease missense mutations in ATP7B affect metal-binding domain structural dynamics2019Ingår i: Biometals, ISSN 0966-0844, E-ISSN 1572-8773, Vol. 32, nr 6, s. 875-885Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Wilson disease (WD) is caused by mutations in the gene for ATP7B, a copper transport protein that regulates copper levels in cells. A large number of missense mutations have been reported to cause WD but genotype-phenotype correlations are not yet established. Since genetic screening for WD may become reality in the future, it is important to know how individual mutations affect ATP7B function, with the ultimate goal to predict pathophysiology of the disease. To begin to assess mechanisms of dysfunction, we investigated four proposed WD-causing missense mutations in metal-binding domains 5 and 6 of ATP7B. Three of the four variants showed reduced ATP7B copper transport ability in a traditional yeast assay. To probe mutation-induced structural dynamic effects at the atomic level, molecular dynamics simulations (1.5 mu s simulation time for each variant) were employed. Upon comparing individual metal-binding domains with and without mutations, we identified distinct differences in structural dynamics via root-mean square fluctuation and secondary structure content analyses. Most mutations introduced distant effects resulting in increased dynamics in the copper-binding loop. Taken together, mutation-induced long-range alterations in structural dynamics provide a rationale for reduced copper transport ability.

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