Thermodynamic and Structural Characterization of the Specific Binding of Zn(II) to Human Protein DJ-1

Tashiro, Seiki; Caaveiro, José M. M.; Wu, Chun Xiang; Hoang, Quyen Q.; Tsumoto, Kouhei

doi:10.1021/bi500294h

Cited by 18 publications

(17 citation statements)

References 23 publications

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“…7 ). Similar oxidation of cysteine residues during crystallization has been reported in other crystal structures ( 33 , 34 ). The active site, which is located between the two domains, has the glutathionyl moiety (GS moiety) of the GS-AV substrate sitting on the top of the four β-strands of the N-terminal thioredoxin domain and with the acetoveratrone moiety (AV moiety) of the substrate contacting residues from α4, α8, and a cap loop region, 220 GGGNG 224 , from the C-terminal α-helical domain ( Fig.…”

Section: Resultssupporting

confidence: 84%

Structural and Biochemical Characterization of the Early and Late Enzymes in the Lignin β-Aryl Ether Cleavage Pathway from Sphingobium sp. SYK-6

Pereira

Heins

Gall

et al. 2016

Journal of Biological Chemistry

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There has been great progress in the development of technology for the conversion of lignocellulosic biomass to sugars and subsequent fermentation to fuels. However, plant lignin remains an untapped source of materials for production of fuels or high value chemicals. Biological cleavage of lignin has been well characterized in fungi, in which enzymes that create free radical intermediates are used to degrade this material. In contrast, a catabolic pathway for the stereospecific cleavage of β-aryl ether units that are found in lignin has been identified in Sphingobium sp. SYK-6 bacteria. β-Aryl ether units are typically abundant in lignin, corresponding to 50–70% of all of the intermonomer linkages. Consequently, a comprehensive understanding of enzymatic β-aryl ether (β-ether) cleavage is important for future efforts to biologically process lignin and its breakdown products. The crystal structures and biochemical characterization of the NAD-dependent dehydrogenases (LigD, LigO, and LigL) and the glutathione-dependent lyase LigG provide new insights into the early and late enzymes in the β-ether degradation pathway. We present detailed information on the cofactor and substrate binding sites and on the catalytic mechanisms of these enzymes, comparing them with other known members of their respective families. Information on the Lig enzymes provides new insight into their catalysis mechanisms and can inform future strategies for using aromatic oligomers derived from plant lignin as a source of valuable aromatic compounds for biofuels and other bioproducts.

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Section: Resultssupporting

confidence: 84%

Structural and Biochemical Characterization of the Early and Late Enzymes in the Lignin β-Aryl Ether Cleavage Pathway from Sphingobium sp. SYK-6

Pereira

Heins

Gall

et al. 2016

Journal of Biological Chemistry

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“…Human DJ-1 and muteins were cloned in a modified pET28b vector containing an N-terminal His 6 -tag and a TEV cleavage site between the N-terminal tag and the sequence of the protein. 28 Briefly, Escherichia coli BL21 (DE3) transformed with plasmid containing DJ-1 was grown in LB medium at 37 °C. Protein expression was induced with isopropyl β-D-thiogalactopyranoside (1 mM) when OD 600 reached a value of 0.6.…”

Section: Methodsmentioning

confidence: 99%

“…The thermal stability of DJ-1 in the presences or absence of compounds was monitored by DSF with SYPRO Orange (Invitrogen), in a CFX Connect Real-Time System (Bio-Rad). 28 Excitation and emission filters were set to 470 and 570 nm, respectively. Compounds were dissolved in DMSO at 2 mM, and stored at −30 ˚C until use.…”

Section: Methodsmentioning

confidence: 99%

Discovery and Optimization of Inhibitors of the Parkinson’s Disease Associated Protein DJ-1

et al. 2018

Self Cite

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DJ-1 is a Parkinson's disease associated protein endowed with enzymatic, redox sensing, regulatory, chaperoning, and neuroprotective activities. Although DJ-1 has been vigorously studied for the past decade and a half, its exact role in the progression of the disease remains uncertain. In addition, little is known about the spatiotemporal regulation of DJ-1, or the biochemical basis explaining its numerous biological functions. Progress has been hampered by the lack of inhibitors with precisely known mechanisms of action. Herein, we have employed biophysical methodologies and X-ray crystallography to identify and to optimize a family of compounds inactivating the critical Cys106 residue of human DJ-1. We demonstrate these compounds are potent inhibitors of various activities of DJ-1 in vitro and in cell-based assays. This study reports a new family of DJ-1 inhibitors with a defined mechanism of action, and contributes toward the understanding of the biological function of DJ-1.

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“…Similar to CCS, DJ‐1 has also been found to associate with the cell membrane, in particular to lipid rafts . Furthermore, DJ‐1 was also found to bind Zn(II) ions in the same binding pocket as Cu(II) ions with a higher binding affinity . Together, these latest findings suggest that DJ‐1 might act to transfer Zn and/or Cu to SOD1 independent of or in conjunction with CCS at the cell membrane.…”

Section: Discussionmentioning

confidence: 79%

Lipid-associated aggregate formation of superoxide dismutase-1 is initiated by membrane-targeting loops

Chng¹,

Strange

2014

Proteins

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Copper-Zinc superoxide dismutase 1 (SOD1) is a homodimeric enzyme that protects cells from oxidative damage. Hereditary and sporadic amyotrophic lateral sclerosis may be linked to SOD1 when the enzyme is destabilized through mutation or environmental stress. The cytotoxicity of demetallated or apo-SOD1 aggregates may be due to their ability to cause defects within cell membranes by co-aggregating with phospholipids. SOD1 monomers may associate with the inner cell membrane to receive copper ions from membrane-bound copper chaperones. But how apo-SOD1 interacts with lipids is unclear. We have used atomistic molecular dynamics simulations to reveal that flexible electrostatic and zinc-binding loops in apo-SOD1 dimers play a critical role in the binding of 1-octanol clusters and phospholipid bilayer, without any significant unfolding of the protein. The apo-SOD1 monomer also associates with phospholipid bilayer via its zinc-binding loop rather than its exposed hydrophobic dimerization interface. Our observed orientation of the monomer on the bilayer would facilitate its association with a membrane-bound copper chaperone. The orientation also suggests how membrane-bound monomers could act as seeds for membrane-associated SOD1 aggregation.

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Thermodynamic and Structural Characterization of the Specific Binding of Zn(II) to Human Protein DJ-1

Cited by 18 publications

References 23 publications

Structural and Biochemical Characterization of the Early and Late Enzymes in the Lignin β-Aryl Ether Cleavage Pathway from Sphingobium sp. SYK-6

Structural and Biochemical Characterization of the Early and Late Enzymes in the Lignin β-Aryl Ether Cleavage Pathway from Sphingobium sp. SYK-6

Discovery and Optimization of Inhibitors of the Parkinson’s Disease Associated Protein DJ-1

Lipid-associated aggregate formation of superoxide dismutase-1 is initiated by membrane-targeting loops

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