Rat liver acyl-CoA synthetase 4 is a peripheral-membrane protein located in two distinct subcellular organelles, peroxisomes, and mitochondrial-associated membrane

Lewin, Tal M.; Horn, Cynthia G. Van; Krisans, Skaidrite K.; Coleman, Rosalind A.

doi:10.1016/s0003-9861(02)00247-3

Cited by 127 publications

(110 citation statements)

References 37 publications

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“…43 To further confirm that PS1 is a MAM-enriched protein, we compared the immunocytochemical localization of PS1 in human fibroblasts with that of FACL4, a known MAM-localized protein. 24 We first stained cells with MT Red and then detected FACL4 by immunocytochemistry ( Figure 3A). We found that FACL4 immunostain (green) "co-localized" with MT Red (red), but only partially: the "colocalization" was most predominant in the region around the nucleus (yellow arrowhead in Figure 3A), but not in the more distal regions of the cell (red arrowhead in Figure 3A).…”

Section: Resultsmentioning

confidence: 99%

“…16 More than two dozen proteins are concentrated in MAM (see Supplemental Table S1 at http://ajp.amjpathol.org), 15,[17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] including proteins involved in calcium homeostasis (eg, inositol triphosphate receptor isoform 3), in lipid metabolism (eg, fatty acid co-A ligase 4 [FACL4]), in intermediate metabolism (eg, glucose-6-phosphatase), in cholesterol metabolism (eg, acyl-coenzyme A:cholesterol acyltransferase 1), and in the transfer of lipids between the ER and mitochondria. A few nonenzymatic proteins are also concentrated in MAM (see Supplemental Table S1 at http://ajp.amjpathol.org), 15,[17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] suggesting that it is a domain of the ER with specialized functions. Contacts between the two organelles are maintained by MAMassociated proteins, such as phosphofurin acidic cluster sorting protein 2, which controls the apposition of mitochondria with the ER and which appears to stabilize and regulate the interaction of ER and mitochondria.…”

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confidence: 99%

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Presenilins Are Enriched in Endoplasmic Reticulum Membranes Associated with Mitochondria

Area‐Gómez

Groof

Boldogh

et al. 2009

The American Journal of Pathology

344

305

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Presenilin-1 (PS1) and -2 (PS2), which when mutated cause familial Alzheimer disease, have been localized to numerous compartments of the cell, including the endoplasmic reticulum, Golgi, nuclear envelope, endosomes, lysosomes, the plasma membrane, and mitochondria. Using three complementary approaches, subcellular fractionation, ␥-secretase activity assays, and immunocytochemistry, we show that presenilins are highly enriched in a subcompartment of the endoplasmic reticulum that is associated with mitochondria and that forms a physical bridge between the two organelles, called endoplasmic reticulum-mitochondria-associated membranes. A localization of PS1 and PS2 in mitochondria-associated membranes may help reconcile the disparate hypotheses regarding the pathogenesis of Alzheimer disease and may explain many seemingly unrelated features of this devastating neurodegenerative disorder. Alzheimer disease (AD) is a late onset neurodegenerative disorder characterized by progressive neuronal loss, especially in the cortex and the hippocampus. 1 The two main histopathological hallmarks of AD are the accumulation of extracellular neuritic plaques, consisting predominantly of ␤-amyloid (A␤), and of neurofibrillary tangles, consisting mainly of hyperphosphorylated forms of the microtubule-associated protein tau. 1The vast majority of AD is sporadic, but mutations in amyloid precursor protein (APP), presenilin-1 (PS1), and presenilin-2 (PS2) have been identified in the rarer familial form, which is similar to sporadic AD but has an earlier age of onset.PS1 and PS2 are aspartyl proteases that cleave their substrates within transmembrane regions. The active forms of PS1 and PS2 are N-and C-terminal fragments, which are produced by cleavage of full-length presenilin in its "loop" domain.2 PS1 and PS2 are components of the ␥-secretase complex that processes a number of plasma-membrane proteins, including Notch, Jagged, E-cadherin, and, most relevant to AD, APP. The ␥-secretase complex also contains three other structural subunits: APH1, nicastrin (also called APH2), and presenilin enhancer protein 2.2 Following cleavage of APP by ␤-secretase, ␥-secretase cleaves the ϳ100-aa C-terminal "␤-stub" to release small amyloidogenic fragments, 40-and 42-aa in length (A␤40 and A␤42), that have been implicated in the pathogenesis of AD, as well as a ϳ60-aa APP intracellular domain.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Presenilins Are Enriched in Endoplasmic Reticulum Membranes Associated with Mitochondria

Area‐Gómez

Groof

Boldogh

et al. 2009

The American Journal of Pathology

344

305

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“…Rat ACSL4 is a membrane-associated long chain acyl-CoA synthetase [8] that can activate both saturated and unsaturated fatty acids from 14 to 26 carbons [9]. In human brain a longer splice variant is present and mutations are associated with a rare form of X-linked mental retardation [10,11].…”

Section: Introductionmentioning

confidence: 99%

Mutagenesis of rat acyl-CoA synthetase 4 indicates amino acids that contribute to fatty acid binding

Stinnett

Lewin

Coleman

2007

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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SummaryAlthough each of the five mammalian long-chain acyl-CoA synthetases (ACSL) can bind saturated and unsaturated fatty acids ranging from 12 to 22 carbons, ACSL4 prefers longer chain polyunsaturated fatty acids. In order to gain a better understanding of ACSL4 fatty acid binding, we based a mutagenesis approach on sequence alignments related to ttLC-FACS crystallized from Thermus thermophilus HB8. Four residues selected for mutagenesis corresponded to residues in ttLC-FACS that comprise the fatty acid binding pocket; the fifth residue aligned with a region thought to be involved in fatty acid selectivity of the Escherichia coli acyl-CoA synthetase, FadD. Changing an amino acid at the entry of the putative fatty acid binding pocket, G401L, resulted in an inactive enzyme. Mutating a residue near the pocket entry, L399M, did not significantly alter enzyme activity, but mutating a residue at the hydrophobic terminus of the pocket, S291Y, altered ACSL4's preference for 20:5 and 22:6 and increased its apparent Km for ATP. Mutating a site in a region previously identified as important for fatty acid binding also altered activation of 20:4 and 20:5. These studies suggested that the preference of ACSL4 for long-chain polyunsaturated fatty acids can be modified by altering specific amino acid residues.

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“…Except for ACS4 (41), the rat ACSs are, or are predicted to be, integral membrane proteins that have active sites facing the cytosol (42). Like FadD, the ACSs use a broad range of fatty acid substrates from 10 to 22 carbons, but they are differentially inhibited by triacsin C and thiazolidinediones and are believed to link acyl-CoAs to different and distinct fates within mammalian cells (2).…”

Section: Discussionmentioning

confidence: 99%

Rat Long Chain Acyl-CoA Synthetase 5, but Not 1, 2, 3, or 4, Complements Escherichia coli fadD

Caviglia

Wang

et al. 2004

Journal of Biological Chemistry

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Long chain fatty acids are converted to acyl-CoAs by acyl-CoA synthetase (fatty acid CoA ligase: AMP forming, E.C. 6.2.1.3; ACS). Escherichia coli has a single ACS, FadD, that is essential for growth when fatty acids are the sole carbon and energy source. Rodents have five ACS isoforms that differ in substrate specificity, tissue expression, and subcellular localization and are believed to channel fatty acids toward distinct metabolic pathways. We expressed rat ACS isoforms 1-5 in an E. coli strain that lacked FadD. All rat ACS isoforms were expressed in E. coli fadD or fadDfadR and had ACS specific activities that were 1.6 -20-fold higher than the wild type control strain expressing FadD. In the fadD background, the rat ACS isoforms 1, 2, 3, 4 and 5 oxidized [ 14 C]oleate at 5 to 25% of the wild type levels, but only ACS5 restored growth on oleate as the sole carbon source. To ensure that enzymes of ␤-oxidation were not limiting, assays of ACS activity, ␤-oxidation, fatty acid transport, and phospholipid synthesis were also examined in a fadD fadR strain, thereby eliminating FadR repression of the transporter FadL and the enzymes of ␤-oxidation. In this strain, fatty acid transport levels were low but detectable for ACS1, 2, 3, and 4 and were nearly 50% of wild type levels for ACS5. Despite increases in ␤-oxidation, only ACS5 transformants were able to grow on oleate. These studies show that although ACS isoforms 1-4 variably supported moderate transport activity, ␤-oxidation, and phospholipid synthesis and although their in vitro specific activities were greater than that of chromosomally encoded FadD, they were unable to substitute functionally for FadD regarding growth. Thus, membrane composition and proteinprotein interactions may be critical in reconstituting bacterial ACS function.

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Rat liver acyl-CoA synthetase 4 is a peripheral-membrane protein located in two distinct subcellular organelles, peroxisomes, and mitochondrial-associated membrane

Cited by 127 publications

References 37 publications

Presenilins Are Enriched in Endoplasmic Reticulum Membranes Associated with Mitochondria

Presenilins Are Enriched in Endoplasmic Reticulum Membranes Associated with Mitochondria

Mutagenesis of rat acyl-CoA synthetase 4 indicates amino acids that contribute to fatty acid binding

Rat Long Chain Acyl-CoA Synthetase 5, but Not 1, 2, 3, or 4, Complements Escherichia coli fadD

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