Structural unification of diverse transmembrane acyltransferases reveals a conserved fold for the Transmembrane Acyl Transferase (TmAT) superfamily

TY - JOUR

T1 - Structural unification of diverse transmembrane acyltransferases reveals a conserved fold for the Transmembrane Acyl Transferase (TmAT) superfamily

AU - Kinniment-Williams, Bethan

AU - Jurgeleviciute, Vytaute

AU - West, Daniel

AU - Herman, Reyme

AU - Blaza, Jamie

AU - Van Der Woude, Marjan

AU - Thomas, Gavin Hugh

N1 - ©2025 The Authors

PY - 2025/9/1

Y1 - 2025/9/1

N2 - 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.

AB - 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.

U2 - 10.1016/j.jbc.2025.110546

DO - 10.1016/j.jbc.2025.110546

M3 - Article

SN - 0021-9258

VL - 301

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 9

M1 - 110546

ER -