Architecture of an asymmetric short chain/long chain hybrid acyl‑CoA carboxylase from Mycobacterium smegmatis

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Abstract
Mycobacteria comprise an uneven number of genes coding for biotin carboxylase (BC) and acyl-CoA carboxyl transferase (CT) activities and an ε-subunit of unknown function. To unravel the composition of acyl-CoA carboxylase (ACCase) holoenzymes under native conditions, we pulled down endogenously expressed biotinylated proteins from Mycobacterium smegmatis . The extract included an unexpected 16-subunit ACCase holoenzyme, exhibiting distinct long-chain (LC) and short-chain (SC) CT activities. It consists of a central two-layered CT (AccD4)₂/(AccD5)₄ assembly that interacts with a C-terminal AccE5 dimer within its central hole. On each CT hexamer face, an asymmetric BC AccA3 tetramer is connected through a flexible AccE5 segment. This is preceded by a folded AccE5 segment that contributes to an asymmetric nine-stranded β−barrel with contributions from all four AccA3 subunits. This barrel allows the BC assembly to rotate ~90 o in the presence of acyl-CoA substrates. These data demonstrate that asymmetric, multi-substrate ACCases differ fundamentally from symmetric, single-substrate ACCases.

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