Structural unification of diverse transmembrane acyltransferases reveals a conserved fold for the transmembrane acyl transferase (TmAT) superfamily.

The movement of acyl groups across biological membranes is essential for many cellular processes. One major family of proteins catalysing this reaction are the acyl transferase family 3 (AT3) proteins, which form a pore to allow acyl-CoA to penetrate the membrane for transfer onto an extracytosolic acceptor molecule. Recent structures of the sequence-unrelated human heparan-α-glucosaminide N-acetyltransferase (HGSNAT) support a similar transmembrane acyl-group transfer mechanism. Here we demonstrate that both protein families contain a conserved 10-transmembrane helical fold with high structural and detectable sequence conservation around the acyl-CoA pore, supporting the previously proposed Transmembrane Acyl Transferase (TmAT) protein superfamily. In addition, we identify TmAT proteins, including the human Golgi sialate-O-acetyltransferase (CASD1), the human/fungal PIG-W/GWT1 enzymes and the bacterial vancomycin resistance protein VanTG, where the TmAT domain's function has been largely unrecognised. We conclude that the TmAT fold represents an ancient architecture for transmembrane acyl-group transfer with important roles in the dynamic modification of glycans in diverse processes across the three domains of life.