The Lysophospholipid Acyltransferase Antagonist CI‐976 Inhibits a Late Step in COPII Vesicle Budding

Brown, William J.; Plutner, Helen; Drecktrah, Daniel; Judson, Bret L.; Balch, William E.

doi:10.1111/j.1600-0854.2008.00711.x

Cited by 36 publications

(24 citation statements)

References 57 publications

(105 reference statements)

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“…For this purpose, mutants were overexpressed in cells expressing vesicular stomatitis virus glycoprotein (VSV-G), a type 1 transmembrane protein that is efficiently transported between the ER and the Golgi in a p115-dependent fashion 36,37,39,46,56,78. Overexpression (∼10-fold), using a vaccinia transient expression system in the presence of the Sar1-H79G dominant negative mutant that inhibits COPII vesicle formation79,80, prevents export VSV-G from the ER and acquisition of endoglycosidase H (endo H) resistance, a hallmark of processing by cis Golgi α-mannosidases and glycosidases81-83 (Fig. 6C).…”

Section: Resultsmentioning

confidence: 99%

Structural and Functional Analysis of the Globular Head Domain of p115 Provides Insight into Membrane Tethering

Chen

Moyer

et al. 2009

Journal of Molecular Biology

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Molecular tethers play a central role in the organization of the complex membrane architecture of eukaryotic cells. p115 is a ubiquitous, essential tether involved in vesicle transport and the structural organization of the exocytic pathway. We describe two crystal structures of the N-terminal domain of p115 at 2.0 Å resolution. The p115 structures show a novel α-solenoid architecture constructed of 12 armadillo-like, tether-repeat (TR), α-helical tripod motifs. We find that the H1 TR binds the Rab1 GTPase involved in ER to Golgi transport. Mutation of the H1 motif results in the dominant negative inhibition of ER to Golgi trafficking. We propose that the H1 helical tripod contributes to the assembly of Rab-dependent complexes responsible for the tether and SNARE-dependent fusion of membranes.

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Section: Resultsmentioning

confidence: 99%

Structural and Functional Analysis of the Globular Head Domain of p115 Provides Insight into Membrane Tethering

Chen

Moyer

et al. 2009

Journal of Molecular Biology

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“…3B ). The calculated LPCAT activity of phosphosphorylated Prdx6 was 10-fold greater at pH 4 and 27-fold greater at pH 7 than the ( 39,40 ). The results showed a dose dependent inhibition of the LPCAT activity of Prdx6; the percent inhibition was similar for Prdx6 assay at pH 4 and phosphorylated Prdx6 assay at pH 7 with 50% inhibition at approximately 10 M ( Fig.…”

Section: Resultsmentioning

confidence: 99%

A novel lysophosphatidylcholine acyl transferase activity is expressed by peroxiredoxin 6

Fisher

Dodia

Sorokina

et al. 2016

Journal of Lipid Research

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as short chain hydroperoxides) using GSH as an electron donor and for hydrolysis of phospholipids; i.e., it exhibits both GSH peroxidase (GPx) and phospholipase A 2 (PLA 2 ) activities ( 1 ). These activities require the binding of Prdx6 to phospholipids in a specifi c orientation in relation to cys47, the active site for GPx activity, and to S32-H26-D140, the catalytic triad for PLA 2 activity ( 2, 3 ). The GPx activity of Prdx6 plays a key role in the antioxidant defense of the lung, as well as other organs ( 4-8 ), and has been shown recently to participate in the repair of peroxidized cell membranes by reduction of phospholipid hydroperoxides ( 3, 9 ). The PLA 2 activity of Prdx6 also participates in the repair of peroxidized cell membranes by liberating the sn -2 oxidized fatty acid to generate lysophosphatidylcholine (LPC) ( 9, 10 ). Additionally, the PLA 2 activity participates in the turnover of lung surfactant phospholipids with a major function in phospholipid remodeling to generate the dipalmitoylphosphatidylcholine (DPPC) that is the surface-active lipid component of the lung surfactant (11)(12)(13)(14)(15). Both the repair of peroxidized cell membrane phospholipids and a pathway for DPPC synthesis require the combined activity of PLA 2 followed by a LPC acyl transferase (LPCAT) activity in order to either regenerate a reduced membrane phospholipid or to remodel phosphatidylcholine (PC) to produce DPPC . This pathway that combines PLA 2 activity followed by LPCAT activity has been designated as the remodeling pathway for PC synthesis (Lands cycle) ( 16 ).These metabolic functions of PLA 2 that are associated with phospholipid turnover and membrane repair are clearly compartmentalized within cells. While DPPC synthesis via the de novo (Kennedy) pathway occurs in the Peroxiredoxin (Prdx)6 is a 1-cys member of the Prdx family that has the unique combination of activities for both reduction of phospholipid hydroperoxides (as well

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“…Although the nature of the signal controlling rhythmic protein secretion remains to be identified, rhythmic metabolism of food and notably, lipids may underlie this regulation. Indeed, protein secretion is highly regulated by sterol and cholesterol metabolism, at least partly through the activity of acyl-CoA:cholesterol acyltransferase (48,49). In fact, acyl-CoA:cholesterol acyltransferase inhibitors are used as blockers of vesicular traffic between the ER and Golgi (50), and this enzyme exhibits a diurnal activity (51,52) that influences sterol synthesis and potentially, protein secretion.…”

Section: Discussionmentioning

confidence: 99%

Circadian clock-dependent and -independent rhythmic proteomes implement distinct diurnal functions in mouse liver

Mauvoisin

Wang

Jouffe

et al. 2013

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

297

365

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Diurnal oscillations of gene expression controlled by the circadian clock underlie rhythmic physiology across most living organisms. Although such rhythms have been extensively studied at the level of transcription and mRNA accumulation, little is known about the accumulation patterns of proteins. Here, we quantified temporal profiles in the murine hepatic proteome under physiological lightdark conditions using stable isotope labeling by amino acids quantitative MS. Our analysis identified over 5,000 proteins, of which several hundred showed robust diurnal oscillations with peak phases enriched in the morning and during the night and related to core hepatic physiological functions. Combined mathematical modeling of temporal protein and mRNA profiles indicated that proteins accumulate with reduced amplitudes and significant delays, consistent with protein half-life data. Moreover, a group comprising about one-half of the rhythmic proteins showed no corresponding rhythmic mRNAs, indicating significant translational or posttranslational diurnal control. Such rhythms were highly enriched in secreted proteins accumulating tightly during the night. Also, these rhythms persisted in clock-deficient animals subjected to rhythmic feeding, suggesting that food-related entrainment signals influence rhythms in circulating plasma factors.circadian rhythm | proteomics | liver metabolism | posttranslational regulation | protein secretion L ight and heat, the principle energy sources for life, are only periodically available with a period of 1 d. Consequently, organisms acquired a timing system to adapt their physiology and anticipate these diurnal variations. In mammals, this circadian clock influences most aspects of physiology and behavior (1). In humans, perturbations of this clock lead to pathologies, including metabolic and vascular diseases. Although the oscillatory clockwork is cell-autonomous, timing on the scale of organisms uses a hierarchal organization: a master clock within the suprachiasmatic nuclei (SCN) of the hypothalamus receives light input through the retina and communicates timing signals to slave oscillators in other peripheral tissues (2).In mammals, the molecular oscillator uses interconnected transcriptional and translational feedback loops, in which multiple layers of control, including temporal posttranscriptional and posttranslational regulation, play important roles (3). An active area of chronobiology aims at understanding how the temporal signals from the core oscillator are relayed to clock output function. In this context, genome-wide rhythms in mRNA accumulation were characterized in several models. In general, around 10% of the genes, encoding many enzymes involved in different aspects of cellular metabolism, show rhythmic mRNA accumulation, establishing the role of the circadian clock in temporally gating rhythmic physiology (4).However, comparatively little is known on the temporal accumulation of proteins, despite increasing evidence suggesting that posttranscriptional mechanisms also contr...

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The Lysophospholipid Acyltransferase Antagonist CI‐976 Inhibits a Late Step in COPII Vesicle Budding

Cited by 36 publications

References 57 publications

Structural and Functional Analysis of the Globular Head Domain of p115 Provides Insight into Membrane Tethering

Structural and Functional Analysis of the Globular Head Domain of p115 Provides Insight into Membrane Tethering

A novel lysophosphatidylcholine acyl transferase activity is expressed by peroxiredoxin 6

Circadian clock-dependent and -independent rhythmic proteomes implement distinct diurnal functions in mouse liver

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