Dynamics driving function − new insights from electron transferring flavoproteins and partner complexes

Abstract

Electron transferring flavoproteins (ETFs) are soluble heterodimeric FAD-containing proteins that function primarily as soluble electron carriers between various flavoprotein dehydrogenases. ETF is positioned at a key metabolic branch point, responsible for transferring electrons from up to 10 primary dehydrogenases to the membrane-bound respiratory chain. Clinical mutations of ETF result in the often fatal disease glutaric aciduria type II. Structural and biophysical studies of ETF in complex with partner proteins have shown that ETF partitions the functions of partner binding and electron transfer between (a) a 'recognition loop', which acts as a static anchor at the ETF-partner interface, and (b) a highly mobile redox-active FAD domain. Together, this enables the FAD domain of ETF to sample a range of conformations, some compatible with fast interprotein electron transfer. This 'conformational sampling' enables ETF to recognize structurally distinct partners, whilst also maintaining a degree of specificity. Complex formation triggers mobility of the FAD domain, an 'induced disorder' mechanism contrasting with the more generally accepted models of protein-protein interaction by induced fit mechanisms. We discuss the implications of the highly dynamic nature of ETFs in biological interprotein electron transfer. ETF complexes point to mechanisms of electron transfer in which 'dynamics drive function', a feature that is probably widespread in biology given the modular assembly and flexible nature of biological electron transfer systems.

Human METTL20 Is a Mitochondrial Lysine Methyltransferase That Targets the β Subunit of Electron Transfer Flavoprotein (ETFβ) and Modulates Its Activity

“…ETF␣/␤ Methylation Reduces Electron Transfer from AcylCoA Dehydrogenases-ETF␣/␤ acts as a mobile electron carrier that shuttles electrons from 13 different mitochondrial dehydrogenases to ETF:quinone oxidoreductase (16). Apparently, the interaction between ETF␣/␤ and these dehydrogenases is mediated by a recognition loop in ETF␤ encompassing residues 191-200 (18), i.e.…”

“…Structural and biochemical studies indicated residues 191-200 in ETF␤ to form a recognition loop involved in the interaction between ETF and some of the mitochondrial dehydrogenases (16,18). Because Lys 200 and Lys 203 are located adjacent to this ETF␤ recognition loop, one may speculate that ETF␤ methylation may differentially affect its interaction with the various mitochondrial dehydrogenases, thus providing a regulatory mechanism for modulating the metabolism of fatty acids, certain amino acids, and choline.…”

“…Electron transfer flavoprotein (ETF) is a FAD-containing, mitochondrial protein composed of two subunits: ␣ and ␤ (ETF␣ and ETF␤, respectively) (13)(14)(15)(16). ETF acts as a mobile electron carrier that shuttles electrons between several FADcontaining dehydrogenases present in the mitochondrial matrix and the membrane-bound ETF:quinone oxidoreductase (17).…”

The METTL20 Homologue from Agrobacterium tumefaciens Is a Dual Specificity Protein-lysine Methyltransferase That Targets Ribosomal Protein L7/L12 and the β Subunit of Electron Transfer Flavoprotein (ETFβ)

“…Eukaryotic ETF is a mitochondrial protein composed of two subunits, ␣ and ␤ (ETF␣ and ETF␤), and it binds two cofactors, FAD and AMP (15). ETF mediates transfer of electrons from several mitochondrial FAD-containing dehydrogenases (DHs) to the ETF:quinone oxidoreductase (ETF-QO), leading to reduction of the quinone pool of the mitochondrial respiratory chain (15).…”

“…ETF mediates transfer of electrons from several mitochondrial FAD-containing dehydrogenases (DHs) to the ETF:quinone oxidoreductase (ETF-QO), leading to reduction of the quinone pool of the mitochondrial respiratory chain (15). In humans, there are ϳ13 ETF-dependent DHs, including sarcosine dehydrogenase and dimethylglycine dehydrogenase (DMGDH), which are involved in choline metabolism, as well as several acyl-CoA dehydrogenases (ACADs) involved in degradation of amino acids or in ␤-oxidation of fatty acids (e.g.…”