Oxidative phosphorylation conformational coupling

The spatial separation between the components of the electron transport chain and the site of ATP synthesis was incompatible with simple interpretations of the chemical coupling hypothesis. In 1964, Paul Boyer suggested that conformational changes in components in the electron transport system consequent to electron transfer might be coupled to ATP formation, the conformational coupling hypothesis. No evidence for direct association has been forthcoming but conformational changes in the subunits of the FI particle are now included in the current mechanism for oxidative phosphorylation. 

How is the oxidation of NADH coupled to the phosphorylation of ADP It was first suggested that electron transfer leads to the formation of a covalent high-energy intermediate that serves as a high phosphoryl transfer potential compound or to the formation of an activated protein conformation, which then drives ATP synthesis. The search for such intermediates for several decades proved fruitless. 

Throughout this discussion of oxidative phosphorylation, we have assumed that the coupling mechanisms involve the formation of high-energy intermediates. This chemical hypothesis is not accepted by all the chemiosmotic hypothesis of oxidative phosphorylation was proposed by Mitchell in 1961, and in 1966 Boyer [148] proposed a new hypothesis involving conformation coupling. 

Much investigative effort has been directed towards the elucidation of the coupling of the two aspects of oxidative phosphorylation. Historically, three mechanisms have been proposed the chemical coupling hypothesis, the chemiosmotic hypothesis and conformational coupling hypothesis. 

There is some indications that mitochondria possess a mechanism of self-elimination. This function was ascribed to the so-called permeability transition pore (PTP). The PTP is a rather large nonspecific channel located in the inner mitochondrial membrane. The PTP is permeable for compounds of molecular mass <1.5 kDa. The PTP is usually closed. A current point of view is that PTP opening results from some modification and conformation change of the ATP/ADP antiporter. Oxidation of Cys56 in the antiporter seems to convert it to the PTP in a way that is catalyzed by another mitochondrial protein, cyclophilin. When opened, the PTP makes impossible the performance of the main mitochondrial function, i.e., coupling of respiration with ATP synthesis. This is due to the collapse of the membrane potential and pH gradient across the inner mitochondrial membrane that mediate respiratory phosphorylation. Membrane potential is also a driving force for import of... 

Electron micrographs have shown that the conformation of the inner mitochondrial membrane and cristae is distinctly different in the resting and active states. It is well established that the shape of mitochondria is not static. This evidence long supported the idea that conformational changes play a role in the coupling of oxidation and phosphorylation. See the article by Stock et al. and the 1999 article by Filhngame cited in the bibliography at the end of this chapter for more on the structure of ATPase. 

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