Taxonomic distribution of proteins containing TLC domains

The tree below includes only several representative species and genera. The complete taxonomic breakdown of all proteins containing TLC domains can be accessed here. Click the counts or percentage values to display the corresponding proteins.

C26-CoA-dependent ceramide synthesis of Saccharomyces cerevisiae is operated by Lag1p and Lac1p.

Guillas I, Kirchman PA, Chuard R, Pfefferli M, Jiang JC, Jazwinski SM, Conzelmann A
EMBO J. 2001; 20: 2655-65

Lag1p and Lac1p are two highly homologous membrane proteins of the endoplasmic reticulum (ER). When both genes are deleted, cells cannot transport glycosylphosphatidylinositol (GPI)-anchored proteins from the ER to the Golgi at a normal rate. Here we show that microsomes or detergent extracts from lag1lac1 double mutants lack an activity transferring C26 fatty acids from C26-coenzyme A onto dihydrosphingosine or phytosphingosine. As a consequence, in intact cells, the normal ceramides and inositolphosphorylceramides are drastically reduced. lag1lac1 cells compensate for the lack of normal sphingolipids by making increased amounts of C26 fatty acids, which become incorporated into glycerophospholipids. They also contain 20- to 25-fold more free long chain bases than wild type and accumulate very large amounts of abnormally polar ceramides. They make small amounts of abnormal mild base-resistant inositolphospholipids. The lipid remodelling of GPI-anchored proteins is severely compromised in lag1lac1 double mutants since only few and mostly abnormal ceramides are incorporated into the GPI anchors. The participation of Lag1p and Lac1p in ceramide synthesis may explain their role in determining longevity.

Lag1p and Lac1p are essential for the Acyl-CoA-dependent ceramide synthase reaction in Saccharomyces cerevisae.

Schorling S, Vallee B, Barz WP, Riezman H, Oesterhelt D
Mol Biol Cell. 2001; 12: 3417-27

Lag1p and Lac1p are two homologous transmembrane proteins of the endoplasmic reticulum in Saccharomyces cerevisiae. Homologous genes have been found in a wide variety of eukaryotes. In yeast, both genes, LAC1 and LAG1, are required for efficient endoplasmic reticulum-to-Golgi transport of glycosylphosphatidylinositol-anchored proteins. In this study, we show that lag1 Delta lac1 Delta cells have reduced sphingolipid levels due to a block of the fumonisin B1-sensitive and acyl-CoA-dependent ceramide synthase reaction. The sphingolipid synthesis defect in lag1 Delta lac1 Delta cells can be partially corrected by overexpression of YPC1 or YDC1, encoding ceramidases that have been reported to have acyl-CoA-independent ceramide synthesis activity. Quadruple mutant cells (lag1 Delta lac1 Delta ypc1 Delta ydc1 Delta) do not make any sphingolipids, but are still viable probably because they produce novel lipids. Moreover, lag1 Delta lac1 Delta cells are resistant to aureobasidin A, an inhibitor of the inositolphosphorylceramide synthase, suggesting that aureobasidin A may be toxic because it leads to increased ceramide levels. Based on these data, LAG1 and LAC1 are the first genes to be identified that are required for the fumonisin B1-sensitive and acyl-CoA-dependent ceramide synthase reaction.

Homologs of the yeast longevity gene LAG1 in Caenorhabditis elegans and human.

Jiang JC, Kirchman PA, Zagulski M, Hunt J, Jazwinski SM
Genome Res. 1998; 8: 1259-72

LAG1 is a longevity gene, the first such gene to be identified and cloned from the yeast Saccharomyces cerevisiae. A close homolog of this gene, which we call LAC1, has been found in the yeast genome. We have cloned the human homolog of LAG1 with the ultimate goal of examining its possible function in human aging. In the process, we have also cloned a homolog from the nematode worm Caenorhabditis elegans. Both of these homologs, LAG1Hs and LAG1Ce-1, functionally complemented the lethality of a lag1delta lac1delta double deletion, despite low overall sequence similarity to the yeast proteins. The proteins shared a short sequence, the Lag1 motif, and a similar transmembrane domain profile. Another, more distant human homolog, TRAM, which lacks this motif, did not complement. LAG1Hs also restored the life span of the double deletion, demonstrating that it functions in establishing the longevity phenotype in yeast. LAG1Hs mapped to 19p12, and it was expressed in only three tissues: brain, skeletal muscle, and testis. This gene possesses a trinucleotide (CTG) repeat within exon 1. This and its expression profile raise the possibility that it may be involved in neurodegenerative disease. This possibility suggests at least one way in which LAG1Hs might be involved in human aging.

Cloning and characterization of LAG1, a longevity-assurance gene in yeast.

D'mello NP, Childress AM, Franklin DS, Kale SP, Pinswasdi C, Jazwinski SM
J Biol Chem. 1994; 269: 15451-9

The yeast Saccharomyces cerevisiae has a finite life span that is measured by the number of times the individual cell divides. The gene coding for one of several transcripts that are differentially expressed during the replicative life span has been cloned. The nucleotide sequence revealed an open reading frame capable of encoding a transmembrane protein of 411 amino acids that displays no significant similarities to any known proteins. Nevertheless, sequences similar to this gene were found in several mammals, including humans. The transcript levels decreased with replicative age of yeast cells. A gene deletion in haploid cells resulted in a pronounced increase (approximately 50%) in mean and in maximum life span. These results indicate that this gene, which we call LAG1, plays a role in determining yeast longevity.