An unanticipated architecture of the 750-kDa α_β_6 holoenzyme of 3-methylcrotonyl-CoA carboxylase

摘要

3-Methylcrotonyl-CoA carboxylase (MCC), a member of the biotindependent carboxylase superfamily, is essential for the metabolism of leucine, and deficient mutations in this enzyme are linked to methylcrotonylglydnuria (MCG) and other serious diseases in humans~(1-8). MCC has strong sequence conservation with propionylCoA carboxylase (PCC), and their holoenzymes are both 750-kilodalton (kDa) α_β_6 dodecamers. Therefore the architecture of the MCC holoenzyme is expected to be highly similar to that of PCC~9. Here we report the crystal structures of the Pseudomonas aeruginosa MCC (PaMCC) holoenzyme, alone and in complex with coenzyme A. Surprisingly, the structures show that the architecture and overall shape of PaMCC are markedly different when compared to PCC. The a-subunits show trimeric association in the PaMCC holoenzyme, whereas they have no contacts with each other in PCC.Moreover, the positions of the two domains in the P-subunit of PaMCC are swapped relative to those in PCC.