Functional and structural membrane topology of rat liver microsomal glutathione transferase

Andersson, Claes; Weinander, Rolf; Lundqvist, Gerd; DePierre, Joseph W.; Morgenstern, Ralf

doi:10.1016/0167-4838(94)90021-3

Cited by 30 publications

(20 citation statements)

References 21 publications

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“…Membrane topology model for microsomal glutathione transferase. Residues 11-35 constitute an experimentally supported membrane-spanning region since trypsin cleavage at Lys4 has been shown to occur on the lumenal side, whereas Lys41 is cleaved on the cytosolic side (Andersson et al, 1994). Cys49 has also been localized experimentally to the cytosolic side (Andersson et al, 1994).…”

Section: Resultsmentioning

confidence: 99%

The projection structure of microsomal glutathione transferase.

1995

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Through the use of electron crystallography, it has been possible to obtain high resolution structural information regarding a mammalian protein that spans the lipid bilayer. Two‐dimensional crystals of the detoxification enzyme microsomal glutathione transferase were induced by slow detergent removal from a mixture containing low amounts of phospholipid. Images of specimens stabilized in tannin were collected using electron cryomicroscopy. The projection structure at 4 A shows tightly packed trimers of the protein. Each of them contains an inner core of six parallel alpha‐helices delineating a central low density region. The helical bundle is partly surrounded by elongated domains.

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Section: Resultsmentioning

confidence: 99%

The projection structure of microsomal glutathione transferase.

1995

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“…In contrast, release of VKOR from the ER membrane required detergent (squares). The detergent concentrations used were also shown to release the two ER integral membrane proteins mGST and mEH, which are both anchored to the membrane by one transmembrane domain (28,29). This shows that some of the VKOR protein components are firmly attached to the ER membrane.…”

Section: Association Of Cytosolic Gsts and Vkor With The Er Membrane-mentioning

confidence: 92%

Assembly of the Warfarin-sensitive Vitamin K 2,3-Epoxide Reductase Enzyme Complex in the Endoplasmic Reticulum Membrane

Cain

Hutson

Wallin

1997

Journal of Biological Chemistry

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␥-Carboxylation of vitamin K-dependent proteins requires a functional vitamin K cycle to produce the active vitamin K cofactor for the ␥-carboxylase which posttranslationally modifies precursors of these proteins to contain ␥-carboxyglutamic acid residues. The warfarinsensitive enzyme vitamin K epoxide reductase (VKOR) of the cycle reduces vitamin K 2,3-epoxide to the active vitamin K hydroquinone cofactor. Because of the importance of warfarin as an anticoagulant in prophylactic medicine and as a poison in rodent pest control, numerous attempts have been made to understand the molecular mechanism underlying warfarin-sensitive vitamin K 2,3-epoxide reduction. In search for protein components that could be involved in this reaction we designed an in vitro ␥-carboxylation test system where the warfarin-sensitive VKOR produces the cofactor for the ␥-carboxylase. Dissection of this system by chromatographic techniques has identified a member(s) of the glutathione S-transferase gene family as one component of the VKOR enzyme complex in the endoplasmic reticulum membrane. The affinity-purified glutathione Stransferase(s) was sensitive to warfarin but lost its warfarin sensitivity and glutathione S-transferase activity upon association with lipids in the presence of Mn 2؉ or Ca 2؉. In the ␥-carboxylation test system, loss of warfarin-sensitive glutathione S-transferase activity coincided with formation of the VKOR enzyme complex. It is proposed that formation of VKOR in the endoplasmic reticulum membrane resembles formation of the lipoxygenase enzyme complex where the glutathione S-transferase-related FLAP protein binds cytosolic lipoxygenase to form a membrane enzyme complex.

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“…Depending on the prediction programme applied, three or four transmembrane regions can be seen in hydropathy plots. One transmembrane stretch was shown by trypsin cleavage of the trimer to be situated between Lys4 and Lys41, with the N‐terminus on the lumenal side of the membrane (Andersson et al ., 1994).…”

Section: Introductionmentioning

confidence: 99%

The three-dimensional map of microsomal glutathione transferase 1 at 6 A resolution

Schmidt-Krey

2000

The EMBO Journal

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Microsomal glutathione transferase 1 (MGST1) is representative of a superfamily of membrane proteins where different members display distinct or overlapping physiological functions, including detoxication of reactive electrophiles (glutathione transferase), reduction of lipid hydroperoxides (glutathione peroxidase), and production of leukotrienes and prostaglandin E. It follows that members of this superfamily constitute important drug targets regarding asthma, inflammation and the febrile response. Here we propose that this superfamily consists of a new class of membrane proteins built on a common left-handed four-helix bundle motif within the membrane, as determined by electron crystallography of MGST1 at 6 A resolution. Based on the 3D map and biochemical data we discuss a model for the membrane topology. The 3D structure differs significantly from that of soluble glutathione transferases, which display overlapping substrate specificity with MGST1.

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Functional and structural membrane topology of rat liver microsomal glutathione transferase

Cited by 30 publications

References 21 publications

The projection structure of microsomal glutathione transferase.

The projection structure of microsomal glutathione transferase.

Assembly of the Warfarin-sensitive Vitamin K 2,3-Epoxide Reductase Enzyme Complex in the Endoplasmic Reticulum Membrane

The three-dimensional map of microsomal glutathione transferase 1 at 6 A resolution

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