Crystallographic Studies of Human MitoNEET

Hou, Xiaowei; Liu, Ru-Juan; Ross, Stuart A.; Smart, Elizabeth; Zhu, Haining; Gong, Weimin

doi:10.1074/jbc.c700172200

Cited by 92 publications

(116 citation statements)

References 37 publications

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“…In addition, the LPS-induced increase in mitoNEET as well as proton shuttling from increased UCP2 may cause the release of mitoNEET's iron sulfur clusters, which would increase free iron and lead to mitochondrial localized oxidative stress. Thus, pioglitazone may bind to mitoNEET [9] to stabilize the iron sulfur clusters [20,28], and this would provide some of the protection against mitochondrial impairment that we previously reported [22]. This hypothesis appears to have potential validity, as mitoNEET may serve as a framework upon which mitochondrial metabolism can be controlled [9,29].…”

Section: Discussionmentioning

confidence: 91%

Protective properties afforded by pioglitazone against intrastriatal LPS in Sprague–Dawley rats

Hunter

Choi

Ross

et al. 2008

Neuroscience Letters

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We created an inflammation-induced Parkinson's disease model, where microglia activation leads to oxidative stress, mitochondrial dysfunction, and dopaminergic neurodegeneration in the substantia nigra. Pioglitazone, an agonist of peroxisome proliferator activated receptor-gamma (PPAR-γ), can prevent these deficits and protect dopaminergic neurons. To continue exploring the effects of pioglitazone in this model we focused on the expression of PPAR-γ, uncoupling protein 2 (UCP2), and mitoNEET. We report that intrastriatal lipopolysaccharide (LPS) increases striatal PPAR-γ, UCP2, and mitoNEET expression, and pioglitazone attenuates these LPS-induced changes.

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Section: Discussionmentioning

confidence: 91%

Protective properties afforded by pioglitazone against intrastriatal LPS in Sprague–Dawley rats

Hunter

Choi

Ross

et al. 2008

Neuroscience Letters

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“…They play critical roles as electron transfer proteins in processes such as photosynthesis, cellular respiration, nitrogen fixation (7,8), and catalysis (1). The newest member of the FeS cluster protein family, mitoNEET, is a uniquely folded homodimeric [2Fe-2S] protein, with each monomer bearing a single [2Fe-2S] cluster (9)(10)(11) (Fig. 1A).…”

mentioning

confidence: 99%

Allosteric control in a metalloprotein dramatically alters function

Baxter

Zuris²,

Wang³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Metalloproteins (MPs) comprise one-third of all known protein structures. This diverse set of proteins contain a plethora of unique inorganic moieties capable of performing chemistry that would otherwise be impossible using only the amino acids found in nature. Most of the well-studied MPs are generally viewed as being very rigid in structure, and it is widely thought that the properties of the metal centers are primarily determined by the small fraction of amino acids that make up the local environment. Here we examine both theoretically and experimentally whether distal regions can influence the metal center in the diabetes drug target mitoNEET. We demonstrate that a loop (L2) 20 Å away from the metal center exerts allosteric control over the cluster binding domain and regulates multiple properties of the metal center. Mutagenesis of L2 results in significant shifts in the redox potential of the [2Fe-2S] cluster and orders of magnitude effects on the rate of [2Fe-2S] cluster transfer to an apo-acceptor protein. These surprising effects occur in the absence of any structural changes. An examination of the native basin dynamics of the protein using all-atom simulations shows that twisting in L2 controls scissoring in the cluster binding domain and results in perturbations to one of the cluster-coordinating histidines. These allosteric effects are in agreement with previous folding simulations that predicted L2 could communicate with residues surrounding the metal center. Our findings suggest that long-range dynamical changes in the protein backbone can have a significant effect on the functional properties of MPs.allostery | CISD1 | energy landscape theory | iron-sulfur cluster | protein frustration

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“…There is no direct information available concerning the specific function of the products of the ttha0024-ttha0027 genes [TTHA0025 is a putative (leucine-rich) membrane protein, TTHA0026 is a water-soluble homologue of the mammalian mitoNEET soluble domain (Tth-NEET0026) and TTHA0027 is a putative potassium channel -subunit homologue]. Multiple sequence alignment of selected mitoNEET-like proteins indicates the conservation of one histidine (indicated by a red arrow) and three cysteine residues, which provide the [2Fe-2S](Cys) 3 (His) 1 cluster-binding motif (boxed) in the recombinant human mitoNEET soluble-domain fragment (Lin et al, 2007;Hou et al, 2007;Paddock et al, 2007). The overall sequence identity between Tth-NEET0026 (69 amino acids) and the human mitoNEET soluble domain of known structure (76 amino acids) is 20.3%.…”

Section: Figurementioning

confidence: 99%

“…1). Moreover, the four ligand residues (Cys37, Cys39, Cys48 and His52) in the [2Fe-2S] cluster-binding motif of human mitoNEET (Lin et al, 2007;Hou et al, 2007;Paddock et al, 2007;PDB codes 2qd0, 2r13 and 2qh7) are strictly conserved in the TTHA0026 protein ( Fig. 1), even though TTHA0026 is tentatively categorized as a hypothetical CDGSH-type zinc-finger protein.…”

Section: Introductionmentioning

confidence: 99%

“…Deficiency of mitoNEET expression in mice results in a compromise in the respiratory capacity of cardiac mitochondria . Recent crystallographic studies on the recombinant soluble CDGSH-type zinc-finger-like domain of human mito-NEET at 1.5-1.8 Å resolution (Lin et al, 2007;Hou et al, 2007;Paddock et al, 2007;PDB codes 2qd0, 2r13 and 2qh7) have revealed that the recombinant mitoNEET soluble domain is a homodimer with each subunit binding a unique [2Fe-2S] cluster (but no Zn 2+ ) in a three-cysteine plus one-histidine ligand environment (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Crystallization and preliminary X-ray diffraction studies of the prototypal homologue of mitoNEET (Tth-NEET0026) from the extreme thermophileThermus thermophilusHB8

Kounosu¹,

Iwasaki²,

Baba³

et al. 2008

Acta Cryst Sect F

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MitoNEET (a mammalian mitochondrial outer membrane protein) is a potential pharmacological and clinical target of the insulin-sensitizer pioglitazone. The thermophilic homologue of mitoNEET (TTHA0026) from Thermus thermophilus HB8 has been heterologously overproduced in Escherichia coli and purified as a water-soluble prototypal protein containing the mitoNEETlike [2Fe-2S] cluster. The resultant recombinant protein, named Tth-NEET0026, has been crystallized in its oxidized form by the hanging-drop vapour-diffusion method using 17%(w/v) polyethylene glycol 4000, 8.5%(v/v) 2-propanol, 15%(v/v) glycerol and 0.085 M HEPES-NaOH pH 7.2. The dark reddish crystals diffracted to 1.80 Å resolution and belonged to the tetragonal space group P4 3 2 1 2, with unit-cell parameters a = 45.51, c = 84.26 Å . The asymmetric unit contains one protein molecule.

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Crystallographic Studies of Human MitoNEET

Abstract: MitoNEET was identified as an outer mitochondrial membrane protein that can potentially bind the anti-diabetes drug pioglitazone. The crystal structure of the cytoplasmic mitoNEET (residues 33-108) is determined in this study.

Cited by 92 publications

References 37 publications

Protective properties afforded by pioglitazone against intrastriatal LPS in Sprague–Dawley rats

Protective properties afforded by pioglitazone against intrastriatal LPS in Sprague–Dawley rats

Allosteric control in a metalloprotein dramatically alters function

Crystallization and preliminary X-ray diffraction studies of the prototypal homologue of mitoNEET (Tth-NEET0026) from the extreme thermophileThermus thermophilusHB8

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