Toogood 2004 J Biol Chem
| Toogood HS, van Thiel A, Basran J, Sutcliffe MJ, Scrutton NS, Leys D (2004) Extensive domain motion and electron transfer in the human electron transferring flavoprotein.medium chain Acyl-CoA dehydrogenase complex. J Biol Chem 279:32904-12. https://doi.org/10.1074/jbc.M404884200 |
Toogood HS, van Thiel A, Basran J, Sutcliffe MJ, Scrutton NS, Leys D (2004) J Biol Chem
Abstract: The crystal structure of the human electron transferring flavoprotein (ETF).medium chain acyl-CoA dehydrogenase (MCAD) complex reveals a dual mode of protein-protein interaction, imparting both specificity and promiscuity in the interaction of ETF with a range of structurally distinct primary dehydrogenases. ETF partitions the functions of partner binding and electron transfer between (i) the recognition loop, which acts as a static anchor at the ETF.MCAD interface, and (ii) the highly mobile redox active FAD domain. Together, these enable the FAD domain of ETF to sample a range of conformations, some compatible with fast interprotein electron transfer. Disorders in amino acid or fatty acid catabolism can be attributed to mutations at the protein-protein interface. Crucially, complex formation triggers mobility of the FAD domain, an induced disorder that contrasts with general models of protein-protein interaction by induced fit mechanisms. The subsequent interfacial motion in the MCAD.ETF complex is the basis for the interaction of ETF with structurally diverse protein partners. Solution studies using ETF and MCAD with mutations at the protein-protein interface support this dynamic model and indicate ionic interactions between MCAD Glu(212) and ETF Arg alpha(249) are likely to transiently stabilize productive conformations of the FAD domain leading to enhanced electron transfer rates between both partners.
Selected quotes
- In the mammalian mitochondrial matrix, electron transferring flavoprotein (ETF) 1 links the activity of no less than 10 different dehydrogenases to the respiratory chain by accepting and subsequently transferring electrons to the membrane-bound ETF-ubiquinone oxidoreductase (1). ETF therefore plays a role akin to the function of cytochrome c in the intermembrane space of mitochondria.
- Mitochondrial flavoprotein partners of ETF include the four fatty acyl-CoA dehydrogenases (very long chain, long chain, medium chain (MCAD), and short chain acyl-CoA dehydrogenases) involved in mitochondrial beta-oxidation of fatty acids; isovaleryl-CoA (IVD), glutaryl-CoA (GCDH), and isobutyryl-CoA dehydrogenases involved in amino acid catabolism; and sarcosine and dimethylglycine dehydrogenase involved in 1-carbon metabolism (1).
- .. the flavin dehydrogenases involved in 1-carbon metabolism are structurally and evolutionarily distinct enzymes (5). In addition, the membrane-bound ETF-ubiquinone oxidoreductase is unrelated to either of these dehydrogenase families. The wide range of structurally different partners thus suggests a certain level of promiscuity in ETF binding, similar to that observed with cytochrome c. However, unlike the relatively small 12-kDa electron carrier cytochrome c, the 60-kDa ETF shows a remarkable specificity for its physiological partners.
- .. the FAD is bound noncovalently to domain II, which sits in a shallow bowl created by domains I and III (6).
- Extensive domain motion in the ETF-acyl-CoA dehydrogenase complexes is therefore needed to drive the catabolism of fatty acids.
Labels:
Preparation: Enzyme
Enzyme: Supercomplex, TCA cycle and matrix dehydrogenases
Pathway: F
