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Abstract
The electron transferring flavoprotein/butyryl-CoA dehydrogenase (EtfAB/Bcd) catalyzes the reduction of one crotonyl-CoA and two ferredoxins by two NADH within a flavin-based electron-bifurcating process. Here we report on the X-ray structure of the Clostridium difficile (EtfAB/Bcd)4 complex in the dehydrogenase-conducting D-state, α-FAD (bound to domain II of EtfA) and δ-FAD (bound to Bcd) being 8 Å apart. Superimposing Acidaminococcus fermentans EtfAB onto C. difficile EtfAB/Bcd reveals a rotation of domain II of nearly 80°. Further rotation by 10° brings EtfAB into the bifurcating B-state, α-FAD and β-FAD (bound to EtfB) being 14 Å apart. This dual binding mode of domain II, substantiated by mutational studies, resembles findings in non-bifurcating EtfAB/acyl-CoA dehydrogenase complexes. In our proposed mechanism, NADH reduces β-FAD, which bifurcates. One electron goes to ferredoxin and one to α-FAD, which swings over to reduce δ-FAD to the semiquinone. Repetition affords a second reduced ferredoxin and δ-FADH−, which reduces crotonyl-CoA.
Highlights
The electron transferring flavoprotein/butyryl-CoA dehydrogenase (EtfAB/Butyryl-CoA dehydrogenase (Bcd)) catalyzes the reduction of one crotonyl-CoA and two ferredoxins by two NADH within a flavin-based electron-bifurcating process
All EtfAB/(MCAD)432 and (EtfAB) are composed of three domains; domains I and II are components of the A- or α-subunit, and domain III of the B- or β-subunit. αFAD is located in the mobile domain II and β-FAD sits between the rigid domains I and III
The EtfAB/Bcd complex was found in a heterododecameric (EtfAB/Bcd)[4] state with a molecular mass of ca. 440 kDa (Fig. 2)
Summary
The electron transferring flavoprotein/butyryl-CoA dehydrogenase (EtfAB/Bcd) catalyzes the reduction of one crotonyl-CoA and two ferredoxins by two NADH within a flavin-based electron-bifurcating process. Sites for NADH and ferredoxin binding and found that the α-FAD on domain II acts like an electron seesaw swinging between the B and D states. Domain II only forms a small interface to Bcd mainly involving the EtfB arm but a larger interface to the EtfAB base (Fig. 2).
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