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The biology of TLCD proteins

Figure: Cartoon depiction of a phylogenetic tree of human TLC-domain containing proteins

The Tram-Lag-CLN8 (TLC) domain is a conserved multi-pass transmembrane protein domain found in plants, yeast, and animals. In humans, there are 16 genes that encode TLC-domain containing proteins. Six of these genes encode ceramide synthase enzymes that catalyse the formation of ceramides, which are structural lipids that are part of cellular membranes. Another three genes encode TRAM proteins, which are involved in the translocation of nascent protein chains into or through the endoplasmic reticulum membrane. Among the remaining seven TLC-domain containing proteins, CLN8 has been shown to mediate the trafficking of lysosomal enzymes. However, the functions of the remaining TLC-domain containing proteins are currently poorly understood.

Our recent research has demonstrated that TLCD1 and TLCD2 proteins regulate the fatty acyl composition of mitochondrial phosphatidylethanolamine, which is an abundant mitochondrial phospholipid. However, the mechanism of action of these proteins and their importance in mitochondrial biology are still not fully understood. By addressing these questions in our current research, we aim not only to understand the biochemistry of TLCD proteins but also to reveal the fundamental mechanisms by which mitochondria regulate their phospholipid acyl tail composition, and why this regulation is important for mitochondrial function.

Related publication

Petkevicius K#, Palmgren H, Glover MS et al. (2022)
TLCD1 and TLCD2 regulate cellular phosphatidylethanolamine composition and promote the progression of non-alcoholic steatohepatitis
Nat Commun 13(1):6020. doi: 10.1038/s41467-022-33735-6
#corresponding author