Extensive domain motion and electron transfer in the human electron transferring flavoprotein•medium chain acyl-CoA dehydrogenase complex
Extensive domain motion and electron transfer in the human electron transferring flavoprotein•medium chain acyl-CoA dehydrogenase complex
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DOI：
10.1074/jbc.m404884200
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发表时间：
2004-07-30
影响因子：
4.8
通讯作者：
Leys, D
中科院分区：
文献类型：
--
作者：
Toogood, HS;van Thiel, A;Leys, D
人电子转移黄素蛋白（ETF）-中链酰基辅酶A脱氢酶（MCAD）复合物的晶体结构揭示了蛋白质-蛋白质相互作用的双重模式，在ETF与一系列结构上不同的主要脱氢酶的相互作用中赋予特异性和混杂性。ETF在（i）识别环和（ii）高度移动的氧化还原活性FAD结构域之间划分配偶体结合和电子转移的功能，所述识别环在ETF.MCAD界面处充当静态锚。总之，这些使得ETF的FAD结构域能够对一系列构象进行采样，其中一些与快速蛋白质间电子转移相容。氨基酸或脂肪酸催化剂的紊乱可归因于蛋白质-蛋白质界面的突变。至关重要的是，复合物的形成触发了FAD结构域的移动性，这是一种诱导的疾病，与通过诱导的适合机制的蛋白质-蛋白质相互作用的一般模型形成对比。MCAD.ETF复合物中随后的界面运动是ETF与结构多样的蛋白质伴侣相互作用的基础。使用在蛋白质-蛋白质界面处具有突变的ETF和MCAD的溶液研究支持该动态模型，并表明MCAD Glu（212）和ETF Argalpha（249）之间的离子相互作用可能瞬时稳定FAD结构域的生产性构象，导致两个伙伴之间的电子转移速率增强。
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 Argalpha(249) are likely to transiently stabilize productive conformations of the FAD domain leading to enhanced electron transfer rates between both partners.