Coenzyme A is bound to tafazzin - a paradigm change for transacylation
Rosas Jimenez, J. G.; Schiller, J.; Vonck, J.; Hummer, G.; Zickermann, V.
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Cardiolipin (CL) is the signature phospholipid of mitochondria. In an obligatory remodeling process, the mitochondrial transacylase tafazzin exchanges its acyl chains to create the highly unsaturated, mature form of CL. Tafazzin dysfunction causes Barth syndrome, a severe multisystem disorder. We determined the structure of tafazzin at a resolution of 2.2 [A] using cryo-electron microscopy (cryo-EM). Until now, the tafazzin reaction has been thought to be independent of coenzyme A (CoA). However, our structure clearly shows an acyl-CoA molecule bound to tafazzin. To decipher how substrates bind to the active site, we combine cryo-EM with structure predictions and molecular dynamics simulations, giving us detailed insights into a transacylation mechanism mediated by CoA. By providing molecular explanations of tafazzin dysfunction caused by pathogenic mutations, we gain a molecular understanding of Barth syndrome.
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