Abstract:Fatty acyl-CoA reductase 1 (Far1) is a ubiquitously expressed peroxisomal membrane protein that generates the fatty alcohols required for the biosynthesis of ether lipids. Lipid droplet localization of exogenously expressed and endogenous human Far1 was observed by fluorescence microscopy under conditions of increased triglyceride synthesis in tissue culture cells. This unexpected finding was supported further by correlative light electron microscopy and subcellular fractionation. Selective permeabilization, p… Show more
“…3 C and D. This distribution did not shift to lipid droplets ( Fig. 3 E,F), as seen for the human FAR1 protein ( Exner et al, 2019 ) that corresponds to the N-terminal domain of Dictyostelium FARAT. Fig.…”
Section: Resultssupporting
confidence: 62%
“…In contrast, the Dictyostelium FARAT protein is found in peroxisomes ( Figs 3 C,D and 7 ) as also seen for the mammalian DHAP-acyltransferase (DHAPAT) ( Liu et al, 2005 ). From here it does not move to the surface of lipid droplets ( Figs 3 E,F and 7 ) by virtue of its FAR domain, as shown for the human FAR1 protein ( Exner et al, 2019 ). Not much work on DHAPAT has been done in mice ( Rodemer et al, 2003 ), apparently because human patients lacking DHAPAT activity were found among the group carrying peroxisomal biogenesis disorders already 20 years ago ( Ofman et al, 1998 ).…”
Lipids are the building blocks for cellular membranes; they provide signalling molecules for membrane dynamics and serve as energy stores. One path of their synthesis is initiated by glycerol-3-phosphate acyltransferase (GPAT), which in
Dictyostelium
resides on the endoplasmic reticulum. When an excess of fatty acids is present, it redistributes to storage organelles, the lipid droplets. Mutants, where the GPAT was eliminated by homologous recombination, produce fewer lipid droplets and are almost devoid of triacylglycerols (TAG), rendering them more resistant to cell death and cell loss in the developmental stages preceding fruiting body formation. The enzyme most closely related to GPAT is called FARAT, because it combines a fatty acyl-reductase (FAR) and an acyltransferase (AT) domain in its sequence. The protein is confined to the lumen of the peroxisome, where it transfers a fatty acid to dihydroxyacetone-phosphate initiating the synthesis of ether lipids, later completed at the endoplasmic reticulum. A mutant lacking FARAT produces lipid droplets that are devoid of the storage lipid monoalkyl-diacyl-glycerol (MDG), but the efficiency of spore formation in the developmental cycle is largely unaltered. Instead, these mutants are strongly impaired in phagocytosis of yeast particles, which is attributed to reduced synthesis of membrane phospholipids containing ether-linked chains.
“…3 C and D. This distribution did not shift to lipid droplets ( Fig. 3 E,F), as seen for the human FAR1 protein ( Exner et al, 2019 ) that corresponds to the N-terminal domain of Dictyostelium FARAT. Fig.…”
Section: Resultssupporting
confidence: 62%
“…In contrast, the Dictyostelium FARAT protein is found in peroxisomes ( Figs 3 C,D and 7 ) as also seen for the mammalian DHAP-acyltransferase (DHAPAT) ( Liu et al, 2005 ). From here it does not move to the surface of lipid droplets ( Figs 3 E,F and 7 ) by virtue of its FAR domain, as shown for the human FAR1 protein ( Exner et al, 2019 ). Not much work on DHAPAT has been done in mice ( Rodemer et al, 2003 ), apparently because human patients lacking DHAPAT activity were found among the group carrying peroxisomal biogenesis disorders already 20 years ago ( Ofman et al, 1998 ).…”
Lipids are the building blocks for cellular membranes; they provide signalling molecules for membrane dynamics and serve as energy stores. One path of their synthesis is initiated by glycerol-3-phosphate acyltransferase (GPAT), which in
Dictyostelium
resides on the endoplasmic reticulum. When an excess of fatty acids is present, it redistributes to storage organelles, the lipid droplets. Mutants, where the GPAT was eliminated by homologous recombination, produce fewer lipid droplets and are almost devoid of triacylglycerols (TAG), rendering them more resistant to cell death and cell loss in the developmental stages preceding fruiting body formation. The enzyme most closely related to GPAT is called FARAT, because it combines a fatty acyl-reductase (FAR) and an acyltransferase (AT) domain in its sequence. The protein is confined to the lumen of the peroxisome, where it transfers a fatty acid to dihydroxyacetone-phosphate initiating the synthesis of ether lipids, later completed at the endoplasmic reticulum. A mutant lacking FARAT produces lipid droplets that are devoid of the storage lipid monoalkyl-diacyl-glycerol (MDG), but the efficiency of spore formation in the developmental cycle is largely unaltered. Instead, these mutants are strongly impaired in phagocytosis of yeast particles, which is attributed to reduced synthesis of membrane phospholipids containing ether-linked chains.
“…Indeed, mammalian glycerophosphate acyl transferase 4 (GPAT4), which is involved in lipid synthesis, AUP1, which acts in quality control as discussed above, caveolins, which shape membranes, and the oleosins, which coat the LDs of plant seeds, all possess HP motifs. Proteins such as the peroxisomal fatty acyl-CoA reductase 1 may use HHs that are attached parallel to the LD monolayer (Exner et al, 2019) (Fig. 3B).…”
Section: Localization Of Hydrophobic Domains To Ldsmentioning
In the general context of an increasing prevalence of obesityassociated diseases, which follows changing paradigms in food consumption and worldwide use of industry-transformed foodstuffs, much attention has been given to the consequences of excessive fattening on health. Highly related to this clinical problem, studies at the cellular and molecular level are focused on the fundamental mechanism of lipid handling in dedicated lipid droplet (LD) organelles. This Review briefly summarizes how views on LD functions have evolved from those of a specialized intracellular compartment dedicated to lipid storage to exerting a more generalized role in the stress response. We focus on the current understanding of how proteins bind to LDs and determine their function, and on the new paradigms that have emerged from the discoveries of the multiple contact sites formed by LDs. We argue that elucidating the important roles of LD tethering to other cellular organelles allows for a better understanding of LD diversity and dynamics.
“…Proteins moving from the ER to LD surface, contain helical hydrophobic domains (HDs), which are monotopic integral membrane domains embedded only in one face of the membrane. These HDs include helical hairpins, hydrophobic helices, and possibly transmembrane domains not fully crossing a bilayer 11,[19][20][21] . In contrast, soluble proteins often use amphipathic helices (AHs) for binding to LDs.…”
Triacylglycerols (TG) are synthesized at the endoplasmic reticulum (ER) bilayer and packaged into organelles called lipid droplets (LDs). LDs are covered by a single phospholipid monolayer contiguous with the ER bilayer. This connection is used by several monotopic integral membrane proteins, with hydrophobic membrane association domains (HDs), to diffuse between the organelles. However, how proteins partition between ER and LDs is not understood. Here, we employed synthetic model systems and found that HD-containing proteins strongly prefer monolayers and returning to the bilayer is unfavorable. This preference for monolayers is due to a higher affinity of HDs for TG over membrane phospholipids. Protein distribution is regulated by PC/PE ratio via alterations in monolayer packing and HD-TG interaction. Thus, HD-containing proteins appear to non-specifically accumulate to the LD surface. In cells, protein editing mechanisms at the ER membrane would be necessary to prevent unspecific relocation of HD-containing proteins to LDs.
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