Topology and Membrane Association of Lecithin: Retinol Acyltransferase

Moise, Alexander R.; Golczak, Marcin; Imanishi, Yoshikazu; Palczewski, Krzysztof

doi:10.1074/jbc.m608315200

Cited by 57 publications

(63 citation statements)

References 56 publications

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“…To confirm our fluorescence-based, live-cell results using a more conventional method of topology analysis, we used a glycosylation reporter (15). Amino acids 2 to 18 of bovine rhodopsin are highly glycosylated when expressed in the lumen of the ER.…”

Section: Resultsmentioning

confidence: 95%

Topology of Mammalian Isoprenylcysteine Carboxyl Methyltransferase Determined in Live Cells with a Fluorescent Probe

Wright

Court

Mor

et al. 2009

Molecular and Cellular Biology

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Isoprenylcysteine carboxyl methyltransferase (Icmt) is a highly conserved enzyme that methyl esterifies the ␣ carboxyl group of prenylated proteins including Ras and related GTPases. Methyl esterification neutralizes the negative charge of the prenylcysteine and thereby increases membrane affinity. Icmt is an integral membrane protein restricted to the endoplasmic reticulum (ER). The Saccharomyces cerevisiae ortholog, Ste14p, traverses the ER membrane six times. We used a novel fluorescent reporter to map the topology of human Icmt in living cells. Our results indicate that Icmt traverses the ER membrane eight times, with both N and C termini disposed toward the cytosol and with a helix-turn-helix structure comprising transmembrane (TM) segments 7 and 8. Several conserved amino acids that map to cytoplasmic portions of the enzyme are critical for full enzymatic activity. Mammalian Icmt has an N-terminal extension consisting of two TM segments not found in Ste14p and therefore likely to be regulatory. Icmt is a target for anticancer drug discovery, and these data may facilitate efforts to develop small-molecule inhibitors.

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Section: Resultsmentioning

confidence: 95%

Topology of Mammalian Isoprenylcysteine Carboxyl Methyltransferase Determined in Live Cells with a Fluorescent Probe

Wright

Court

Mor

et al. 2009

Molecular and Cellular Biology

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“…Nevertheless, LRAT and CRBPs likely act cooperatively for vitamin A esterification (25). The N-terminal portion and/or the C-terminal portion of LRAT are inserted into the membranes of the ER, exposing remnant hydrophilic portions to the cytosol (26,27). There, CRBPs probably deliver vitamin A to the cytosolic portion of LRAT.…”

Section: Discussionmentioning

confidence: 99%

Massive bowel resection upregulates the intestinal mRNA expression levels of cellular retinol-binding protein II and apolipoprotein A-IV and alters the intestinal vitamin A status in rats

Hebiguchi

Mezaki

Morii

et al. 2015

International Journal of Molecular Medicine

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Abstract. Short bowel (SB) syndrome causes the malabsorption of various nutrients. Among these, vitamin A is important for a number of physiological activities. Vitamin A is absorbed by epithelial cells of the small intestine and is discharged into the lymphatic vessels as a component of chylomicrons and is delivered to the liver. In the present study, we used a rat model of SB syndrome in order to assess its effects on the expression of genes associated with the absorption, transport and metabolism of vitamin A. In the rats with SB, the intestinal mRNA expression levels of cellular retinol-binding protein II (CRBP II, gene symbol Rbp2) and apolipoprotein A-IV (gene symbol Apoa4) were higher than those in the sham-operated rats, as shown by RT-qPCR. Immunohistochemical analysis revealed that absorptive epithelial cells stained positive for both CRBP II and lecithin retinol acyltransferase, which are both required for the effective esterification of vitamin A. In the rats with SB, the retinol content in the ileum and the retinyl ester content in the jejunum were lower than those in the sham-operated rats, as shown by quantitative analysis of retinol and retinyl esters by high performance liquid chromatography. These results suggest that the elevated mRNA expression levels of Rbp2 and Apoa4 in the rats with SB contribute to the effective esterification and transport of vitamin A. IntroductionShort bowel (SB) syndrome occurs as a consequence of malabsorption from an intestinal surface area insufficient to maintain growth and a normal nutritional status (1,2). Intestinal adaptation is a well-known phenomenon that increases the absorptive capacity following surgical resection of the small intestine. The most prominent feature of intestinal adaptation is the proliferation of intestinal cells that increases crypt depth and enlarges the length and width of the villi (3). It is known that micronutrients affect several aspects of intestinal adaptation. Wang et al (4) reported that intestinal adaptation was facilitated by retinoic acid, an active form of vitamin A. The authors demonstrated that the intravenous administration of retinoic acid exerted trophic effects in rats with SB by inhibiting apoptosis and stimulating crypt cell proliferation (4).Vitamin A is a fat-soluble vitamin required for a number of physiological activities. Retinyl esters (REs), animal-derived forms of vitamin A, are hydrolyzed into retinol before entering the absorptive epithelial cells. By contrast, β-carotene, a vegetable-derived form of vitamin A, is converted into retinal after entering the absorptive epithelial cells and is then reduced to retinol within the cells (5). The retinol thus produced binds to cellular retinol-binding protein II (CRBP II, gene symbol Rbp2) in absorptive epithelial cells, forming a retinol-CRBP II complex. This complex is esterified to REs by lecithin retinol acyltransferase (LRAT, gene symbol Lrat). REs are then discharged basolaterally into the lymphatic vessels as a component of chylomicrons and are delivered to ...

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“…Except for the predicted N-and C-terminal transmembrane domain of LRAT [27], the catalytic domains of H-REV107 and LRAT are highly homologous (identity 26%) [28,29] (Fig. 4).…”

Section: Discussionmentioning

confidence: 99%

Solution structure of the N‐terminal catalytic domain of human H‐REV107 – A novel circular permutated NlpC/P60 domain

et al. 2010

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H‐REV107 is a Ca2+‐independent phospholipase A1/2, and it is also a pro‐apoptosis protein belonging to the novel class II tumor suppressor family, H‐REV107‐like family. Here we report the solution structure of the N‐terminal catalytic domain of human H‐REV107, which has a similar architecture to classical NlpC/P60 domains, even though their fold topologies are different due to circular permutation in the primary sequence. The phospholipase active site possesses a structurally conserved Cys–His–His catalytic triad as found in NlpC/P60 peptidases, indicating H‐REV107 should adopt a similar catalytic mechanism towards phospholipid substrates to that of NlpC/P60 peptidases towards peptides. As H‐REV107 is highly similar to lecithin retinol acyltransferase, our study also provides structural insight to this essential enzyme in retinol metabolism.

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Topology and Membrane Association of Lecithin: Retinol Acyltransferase

Cited by 57 publications

References 56 publications

Topology of Mammalian Isoprenylcysteine Carboxyl Methyltransferase Determined in Live Cells with a Fluorescent Probe

Topology of Mammalian Isoprenylcysteine Carboxyl Methyltransferase Determined in Live Cells with a Fluorescent Probe

Massive bowel resection upregulates the intestinal mRNA expression levels of cellular retinol-binding protein II and apolipoprotein A-IV and alters the intestinal vitamin A status in rats

Solution structure of the N‐terminal catalytic domain of human H‐REV107 – A novel circular permutated NlpC/P60 domain

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