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  • Portland Press Ltd.  (4)
  • 2010-2014  (4)
  • Biology  (4)
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  • Portland Press Ltd.  (4)
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  • 2010-2014  (4)
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  • Biology  (4)
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  • 1
    Online Resource
    Online Resource
    A molten globule-to-ordered structure transition of Drosophila melanogaster crammer is required for its ability to inhibit cathepsin
    Portland Press Ltd. ; 2012
    In:  Biochemical Journal Vol. 442, No. 3 ( 2012-03-15), p. 563-572
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 442, No. 3 ( 2012-03-15), p. 563-572
    Abstract: Drosophila melanogaster crammer is a novel cathepsin inhibitor that is involved in LTM (long-term memory) formation. The mechanism by which the inhibitory activity is regulated remains unclear. In the present paper we have shown that the oligomeric state of crammer is pH dependent. At neutral pH, crammer is predominantly dimeric in vitro as a result of disulfide bond formation, and is monomeric at acidic pH. Our inhibition assay shows that monomeric crammer, not disulfide-bonded dimer, is a strong competitive inhibitor of cathepsin L. Crammer is a monomeric molten globule in acidic solution, a condition that is similar to the environment in the lysosome where crammer is probably located. Upon binding to cathepsin L, however, crammer undergoes a molten globule-to-ordered structural transition. Using high-resolution NMR spectroscopy, we have shown that a cysteine-to-serine point mutation at position 72 (C72S) renders crammer monomeric at pH 6.0 and that the structure of the C72S variant highly resembles that of wild-type crammer in complex with cathepsin L at pH 4.0. We have determined the first solution structure of propeptide-like protease inhibitor in its active form and examined in detail using a variety of spectroscopic methods the folding properties of crammer in order to delineate its biomolecular recognition of cathepsin.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    URL: Article
    DOI: 10.1042/BJ20111360
    RVK:
    WA 15000
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2012
    detail.hit.zdb_id: 1473095-9
    SSG: 12
    Location Call Number Limitation Availability
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  • 2
    Online Resource
    Online Resource
    AS160 deficiency causes whole-body insulin resistance via composite effects in multiple tissues
    Portland Press Ltd. ; 2013
    In:  Biochemical Journal Vol. 449, No. 2 ( 2013-01-15), p. 479-489
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 449, No. 2 ( 2013-01-15), p. 479-489
    Abstract: AS160 (Akt substrate of 160 kDa) is a Rab GTPase-activating protein implicated in insulin control of GLUT4 (glucose transporter 4) trafficking. In humans, a truncation mutation (R363X) in one allele of AS160 decreased the expression of the protein and caused severe postprandial hyperinsulinaemia during puberty. To complement the limited studies possible in humans, we generated an AS160-knockout mouse. In wild-type mice, AS160 expression is relatively high in adipose tissue and soleus muscle, low in EDL (extensor digitorum longus) muscle and detectable in liver only after enrichment. Despite having lower blood glucose levels under both fasted and random-fed conditions, the AS160-knockout mice exhibited insulin resistance in both muscle and liver in a euglycaemic clamp study. Consistent with this paradoxical phenotype, basal glucose uptake was higher in AS160-knockout primary adipocytes and normal in isolated soleus muscle, but their insulin-stimulated glucose uptake and overall GLUT4 levels were markedly decreased. In contrast, insulin-stimulated glucose uptake and GLUT4 levels were normal in EDL muscle. The liver also contributes to the AS160-knockout phenotype via hepatic insulin resistance, elevated hepatic expression of phosphoenolpyruvate carboxykinase isoforms and pyruvate intolerance, which are indicative of increased gluconeogenesis. Overall, as well as its catalytic function, AS160 influences expression of other proteins, and its loss deregulates basal and insulin-regulated glucose homoeostasis, not only in tissues that normally express AS160, but also by influencing liver function.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    URL: Article
    DOI: 10.1042/BJ20120702
    RVK:
    WA 15000
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2013
    detail.hit.zdb_id: 1473095-9
    SSG: 12
    Location Call Number Limitation Availability
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  • 3
    Online Resource
    Online Resource
    Phosphorylation-dependent association of the G4-1/G5PR regulatory subunit with IKKβ negatively modulates NF-κB activation through recruitment of protein phosphatase 5
    Portland Press Ltd. ; 2011
    In:  Biochemical Journal Vol. 433, No. 1 ( 2011-01-01), p. 187-196
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 433, No. 1 ( 2011-01-01), p. 187-196
    Abstract: The transcription factor NF-κB (nuclear factor κB) co-ordinates various gene expressions in response to diverse signals and is a critical regulator of inflammation and innate immunity. Several negative regulators of NF-κB have been identified as downstream targets of NF-κB and function as a feedback control of NF-κB activation. A few protein phosphatases have also been shown to inactivate NF-κB activation. However, little is known about how protein phosphatases detect and respond to NF-κB activation. In the present study, we report a regulatory subunit of PP5 (protein phosphatase 5), G4-1, that physically interacts with IKKβ [IκB (inhibitor of NF-κB) kinase β] and negatively regulates NF-κB activation. The association of G4-1 with IKKβ depends on the kinase activity of IKKβ. Mapping of the G4-1-binding domain of IKKβ reveals that the serine-rich domain in the C-terminus of IKKβ is required for G4-1 binding. When seven autophosphorylated serine residues in this domain were mutated to alanine, the mutant form of IKKβ lost its ability to bind G4-1 and was more potent than the wild-type kinase to activate NF-κB. Knockdown of G4-1 enhanced TNFα (tumour necrosis factor α)-induced NF-κB activity, and knockdown of PP5 totally abolished the inhibitory activity of G4-1 on NF-κB activation. The results of the present study suggest that G4-1 functions as an adaptor to recruit PP5 to the phosphorylated C-terminus of activated IKKβ and to down-regulate the activation of IKKβ.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    URL: Article
    DOI: 10.1042/BJ20100247
    RVK:
    WA 15000
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2011
    detail.hit.zdb_id: 1473095-9
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
  • 4
    Online Resource
    Online Resource
    Guanylate cyclase-G, expressed in the Grueneberg ganglion olfactory subsystem, is activated by bicarbonate
    Portland Press Ltd. ; 2010
    In:  Biochemical Journal Vol. 432, No. 2 ( 2010-12-01), p. 267-273
    Details
    In: Biochemical Journal, Portland Press Ltd., Vol. 432, No. 2 ( 2010-12-01), p. 267-273
    Abstract: GC (guanylate cyclase)-G is the most recently identified member of the receptor GC family. However, the regulation of its activity and protein expression in the mammalian olfactory system remains unclear. In the present study, we used a GC-G-specific antibody to validate that the GC-G protein is expressed in Grueneberg ganglion neurons, a newly recognized olfactory subsystem co-expressing other cGMP signalling components such as the cGMP-regulated PDE2A (phosphodiesterase 2A) and the cGMP-gated ion channel CNGA3 (cyclic nucleotide-gated cation channel α-3). Further molecular and biochemical analyses showed that heterologously expressed GC-G protein, specifically the C-terminal cyclase domain, was directly stimulated by bicarbonate in both in vivo cellular cGMP accumulation assays in human embryonic kidney-293T cells and in vitro GC assays with a purified recombinant protein containing the GC domain. In addition, overexpression of GC-G in NG108 neuronal cells resulted in a CO2-dependent increase in cellular cGMP level that could be blocked by treatment with acetazolamide, an inhibitor of carbonic anhydrases, which implies that the stimulatory effect of CO2 requires its conversion to bicarbonate. Together, our data demonstrate a novel CO2/bicarbonate-dependent activation mechanism for GC-G and suggest that GC-G may be involved in a wide variety of CO2/bicarbonate-regulated biological processes such as the chemosensory function in Grueneberg ganglion neurons.
    Type of Medium: Online Resource
    ISSN: 0264-6021 , 1470-8728
    URL: Article
    DOI: 10.1042/BJ20100617
    RVK:
    WA 15000
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2010
    detail.hit.zdb_id: 1473095-9
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
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