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  • br DGAT protein interactions Although


    DGAT-protein interactions Although DGAT1 and DGAT2 are Benzydamine HCl australia membrane proteins of the ER, the ER contains within its extensive three-dimensional network different, unique structural and functional protein domains that arise from the non-uniformity imposed on it by the intracellular structures it interacts with [96]. The two DGATs of the tung tree (Vernicia fordii) are located in different regions of the ER [97] and, although the same is yet to be demonstrated in an animal model, it contributes to the idea that the differentiated contributions of the DGAT enzymes are, at least in part, a result of the other proteins they interact with. On the ER, DGAT2 is localized near the surface of the LD as part of a multimeric complex enriched in mitochondrial-associated membranes (MAM) [80], specialised regions of the ER membrane with distinct biochemical properties and with what appear as ER tubules closely juxtaposed to mitochondria on electron micrographs [98]. The co-localization of DGAT2 and mitochondria has been confirmed by biochemical fractionation as well as the presence of a highly conserved, positively charged, putative mitochondrial targeting signal peptide in the DGAT2 amino Benzydamine HCl australia sequence [80]. DGAT2 is enriched in MAM [80] along with other lipid biosynthetic enzymes like phosphatidylethanolamine N-methyltransferase, phosphatidylserine synthase-1 and -2, microsomal triacylglycerol transfer protein, and ACAT1 [[99], [100], [101]]. Besides the MAM domain, DGAT2 has also been reported to localise in the lipid droplet. It is not clear how an integral membrane protein with at least two transmembrane domains translocates from the ER to the LD. Kory et al. [102] have described mechanisms of protein localization to LDs – one such mechanism is the adoption of a V-shaped hairpin conformation that embeds the protein in the ER membrane without the need of a luminal loop to connect the two transmembrane domains. Although it may be a possible mechanism for the translocation of DGAT2 to the LD that could allow DGAT2 to translate or diffuse from the ER membrane to the LD, there has been no experimental evidence to support such a hairpin configuration. McFie et al. [83] demonstrated that the transmembrane domains of DGAT2 completely span the ER membrane and that the amino acid residues between the transmembrane domains are in the ER lumen. This does not explain the fact that DGAT2 resides on the lipid droplet surface itself [103], suggesting an unknown mechanism exists for localizing DGAT2 to the LD. McFie et al. [84] have however identified a separate domain in the C-terminal region of DGAT2, an LD targeting domain, that interacts with LDs. The current model of LD formation suggests the cytoplasmic membrane leaflet of the ER forms the surface of the nascent LD as neutral lipids build-up between the leaflets of the ER membrane, causing the cytoplasmic leaflet to bulge and eventually bud-off from the ER [104]. Based on their observations about the ER and LD targeting sequences in DGAT2, McFie et al. [84] have proposed that the LD targeting domain allows DGAT2 to tether between the ER and LD thereby allowing the channelling of TAGs from its site of synthesis in the ER to the LD where they accumulate and lead to the expansion of the LD. The proposed model is similar to the one proposed for the interaction between DGAT2 localized in the LD and acyl-CoA synthetase-1 (FATP1) localized on the ER – it hypothesizes that there may be a physical interaction between the two enzymes that tethers the ER and the LD [[105], [106], [107]].