Regulation of Membrane Proteins by Dietary Lipids: Effects of Cholesterol and Docosahexaenoic Acid Acyl Chain-Containing Phospholipids on Rhodopsin Stability and Function

Bennett, Michael; Mitchell, Drake C.

doi:10.1529/biophysj.107.122788

Cited by 48 publications

(34 citation statements)

References 65 publications

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“…We suggest that DHA could also modify protein conformation, although we did not find a change in conformation with MHC class I. Nevertheless, a series of experimental studies by several laboratories have shown that DHA can modify the conformation of the G protein-coupled receptor rhodopsin by binding into the grooves between specific helices (39)(40)(41)(42).…”

Section: Discussioncontrasting

confidence: 54%

Docosahexaenoic Acid Modifies the Clustering and Size of Lipid Rafts and the Lateral Organization and Surface Expression of MHC Class I of EL4 Cells

Shaikh

Rockett

Salameh

et al. 2009

The Journal of Nutrition

114

129

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An emerging molecular mechanism by which docosahexaenoic acid (DHA) exerts its effects is modification of lipid raft organization. The biophysical model, based on studies with liposomes, shows that DHA avoids lipid rafts because of steric incompatibility between DHA and cholesterol. The model predicts that DHA does not directly modify rafts; rather, it incorporates into nonrafts to modify the lateral organization and/or conformation of membrane proteins, such as the major histocompatibility complex (MHC) class I. Here, we tested predictions of the model at a cellular level by incorporating oleic acid, eicosapentaenoic acid (EPA), and DHA, compared with a bovine serum albumin (BSA) control, into the membranes of EL4 cells. Quantitative microscopy showed that DHA, but not EPA, treatment, relative to the BSA control diminished lipid raft clustering and increased their size. Approximately 30% of DHA was incorporated directly into rafts without changing the distribution of cholesterol between rafts and nonrafts. Quantification of fluorescence colocalization images showed that DHA selectively altered MHC class I lateral organization by increasing the fraction of the nonraft protein into rafts compared with BSA. Both DHA and EPA treatments increased antibody binding to MHC class I compared with BSA. Antibody titration showed that DHA and EPA did not change MHC I conformation but increased total surface levels relative to BSA. Taken together, our findings are not in agreement with the biophysical model. Therefore, we propose a model that reconciles contradictory viewpoints from biophysical and cellular studies to explain how DHA modifies lipid rafts on several length scales. Our study supports the notion that rafts are an important target of DHA's mode of action.

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Section: Discussioncontrasting

confidence: 54%

Docosahexaenoic Acid Modifies the Clustering and Size of Lipid Rafts and the Lateral Organization and Surface Expression of MHC Class I of EL4 Cells

Shaikh

Rockett

Salameh

et al. 2009

The Journal of Nutrition

114

129

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“…Docosahexaenoic acid is essential to the structure and function of photoreceptor cells in both the retina and the pineal organ (43)(44)(45)(46). Accordingly, VT-AANAT might have functioned to enhance the efficiency of the primitive vertebrate's photodetector by preventing arylalkylamine adduct formation with several essential photodetection molecules.…”

Section: Discussionmentioning

confidence: 99%

Drastic neofunctionalization associated with evolution of the timezyme AANAT 500 Mya

Falcón

Coon

Besseau

et al. 2013

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

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Melatonin (N-acetyl-5-methoxytrypamine) is the vertebrate hormone of the night: circulating levels at night are markedly higher than day levels. This increase is driven by precisely regulated increases in acetylation of serotonin in the pineal gland by arylalkylamine N-acetyltransferase (AANAT), the penultimate enzyme in the synthesis of melatonin. This unique essential role of AANAT in vertebrate timekeeping is recognized by the moniker the timezyme. AANAT is also found in the retina, where melatonin is thought to play a paracrine role. Here, we focused on the evolution of AANAT in early vertebrates. AANATs from Agnathans (lamprey) and Chondrichthyes (catshark and elephant shark) were cloned, and it was found that pineal glands and retinas from these groups express a form of AANAT that is compositionally, biochemically, and kinetically similar to AANATs found in bony vertebrates (VT-AANAT). Examination of the available genomes indicates that VT-AANAT is absent from other forms of life, including the Cephalochordate amphioxus. Phylogenetic analysis and evolutionary rate estimation indicate that VT-AANAT evolved from the nonvertebrate form of AANAT after the Cephalochordate-Vertebrate split over one-half billion years ago. The emergence of VT-AANAT apparently involved a dramatic acceleration of evolution that accompanied neofunctionalization after a duplication of the nonvertebrate AANAT gene. This scenario is consistent with the hypotheses that the advent of VT-AANAT contributed to the evolution of the pineal gland and lateral eyes from a common ancestral photodetector and that it was not a posthoc recruitment.E yes have evolved in all animals to facilitate interactions with the photic environment (1, 2). However, among animals, vertebrates are unique in that they also possess a photoneuroendocrine structure, the pineal gland (3). It converts the 24-h rhythm in environmental lighting into a 24-h rhythm in circulating melatonin, thereby providing a unique and valuable signal of the photic environment. The details of pineal evolution are not clear (4, 5). However, it has been posited that an essential element was arylalkylamine N-acetyltransferase (AANAT; E.C. 2.3.1.87), the penultimate enzyme in the melatonin biosynthesis pathway (6-8); this scenario is referred to as the AANAT hypothesis of pineal evolution (7,8).AANAT catalyzes the N-acetylation of arylalkylamines using acetyl CoA (AcCoA) as the acetyl group donor. The AANAT family, which belongs to the GCN5 superfamily (9, 10), is composed of two subfamilies termed vertebrate (VT) AANAT and nonvertebrate (NV) AANAT. † This nomenclature reflects the phylogenetic distribution of the family members (13-17). The most striking differences between VT-and NV-AANAT are found in regulatory and catalytic regions of the encoded proteins (Fig. 1), consistent with different metabolic roles (7,8).The NV-AANAT is thought to perform a detoxification function through acetylation of a broad range of endogenous and exogenous arylalkylamines and polyamines (13-16). It has been fo...

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“…(58) More recently, the concentration of cholesterol and docosahexaenoic acid (DHA) containing lipids have been shown specifically to affect the properties of rhodopsin from retinal rod cells. (31) In this recent study, rhodopsin reconstituted into artificial lipid assemblies, containing varying concentrations of these two biomolecules, exhibited changes in its denaturation temperature dependent upon the bilayer composition. Increased cholesterol appeared to stabilize the protein.…”

Section: Resultsmentioning

confidence: 90%

“…Membranes containing both cholesterol and the poly-unsaturated docosahexaenoic acid containing lipids have been shown to impact the stability of embedded rhodopsin molecules. (31) Additionally, phenotypes that are deficient in polyunsaturated acids and cholesterol have been linked to visual disfunction. (32) (22) Given the importance of these species in regulating rhodopsin, increased understanding of the distribution of these lipids in intact cells may provide further insight into role of lipid environments that regulate protein function.…”

Section: Introductionmentioning

confidence: 99%

Raman Spectroscopic Imaging of Cholesterol and Docosahexaenoic Acid Distribution in the Retinal Rod Outer Segment

Schultz¹

2011

Aust. J. Chem.

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Raman vibrational spectroscopic imaging was performed on retinal rod cells isolated from bullfrogs (Rana catesbeiana). The Raman spectra enable determination of the lipid and protein rich rod outer segment (ROS) from the nucleus and inner segment of the cell. Peak fitting analysis of spectra obtained from individual rod photoreceptor cells show characteristic vibrational modes that can be associated with cholesterol and docosahexaenoic acid containing lipids. These results provide direct observations of biomolecular gradients in the rod photoreceptor cells, which, thus far, have been based on indirect detergent extracts and histochemical analysis with indicators such as filipin. The detected biomolecules are associated with regulation of the integral membrane protein rhodopsin, and methods capable direct observation of these biomolecules offer new routes to exploring their role in the regulation of cellular processes.

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Regulation of Membrane Proteins by Dietary Lipids: Effects of Cholesterol and Docosahexaenoic Acid Acyl Chain-Containing Phospholipids on Rhodopsin Stability and Function

Cited by 48 publications

References 65 publications

Docosahexaenoic Acid Modifies the Clustering and Size of Lipid Rafts and the Lateral Organization and Surface Expression of MHC Class I of EL4 Cells

Docosahexaenoic Acid Modifies the Clustering and Size of Lipid Rafts and the Lateral Organization and Surface Expression of MHC Class I of EL4 Cells

Drastic neofunctionalization associated with evolution of the timezyme AANAT 500 Mya

Raman Spectroscopic Imaging of Cholesterol and Docosahexaenoic Acid Distribution in the Retinal Rod Outer Segment

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