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How azide inhibits ATP hydrolysis by the F-ATPases.

ABSTRACT: In the structure of bovine F1-ATPase determined at 1.95-A resolution with crystals grown in the presence of ADP, 5'-adenylyl-imidodiphosphate, and azide, the azide anion interacts with the beta-phosphate of ADP and with residues in the ADP-binding catalytic subunit, betaDP. It occupies a position between the catalytically essential amino acids, beta-Lys-162 in the P loop and the "arginine finger" residue, alpha-Arg-373, similar to the site occupied by the gamma-phosphate in the ATP-binding subunit, betaTP. Its presence in the betaDP-subunit tightens the binding of the side chains to the nucleotide, enhancing its affinity and thereby stabilizing the state with bound ADP. This mechanism of inhibition appears to be common to many other ATPases, including ABC transporters, SecA, and DNA topoisomerase IIalpha. It also explains the stimulatory effect of azide on ATP-sensitive potassium channels by enhancing the binding of ADP.

SUBMITTER: Bowler MW

PROVIDER: S-EPMC1469772 | biostudies-literature | 2006 Jun

REPOSITORIES: biostudies-literature

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How azide inhibits ATP hydrolysis by the F-ATPases.

Bowler Matthew W MW Montgomery Martin G MG Leslie Andrew G W AG Walker John E JE

Proceedings of the National Academy of Sciences of the United States of America 20060525 23

In the structure of bovine F1-ATPase determined at 1.95-A resolution with crystals grown in the presence of ADP, 5'-adenylyl-imidodiphosphate, and azide, the azide anion interacts with the beta-phosphate of ADP and with residues in the ADP-binding catalytic subunit, betaDP. It occupies a position between the catalytically essential amino acids, beta-Lys-162 in the P loop and the "arginine finger" residue, alpha-Arg-373, similar to the site occupied by the gamma-phosphate in the ATP-binding subun ...[more]

PMID: 16728506

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Project description:Neuronal computations strongly depend on inhibitory interactions. One such example occurs at the first retinal synapse, where horizontal cells inhibit photoreceptors. This interaction generates the center/surround organization of bipolar cell receptive fields and is crucial for contrast enhancement. Despite its essential role in vision, the underlying synaptic mechanism has puzzled the neuroscience community for decades. Two competing hypotheses are currently considered: an ephaptic and a proton-mediated mechanism. Here we show that horizontal cells feed back to photoreceptors via an unexpected synthesis of the two. The first one is a very fast ephaptic mechanism that has no synaptic delay, making it one of the fastest inhibitory synapses known. The second one is a relatively slow (τ≈200 ms), highly intriguing mechanism. It depends on ATP release via Pannexin 1 channels located on horizontal cell dendrites invaginating the cone synaptic terminal. The ecto-ATPase NTPDase1 hydrolyses extracellular ATP to AMP, phosphate groups, and protons. The phosphate groups and protons form a pH buffer with a pKa of 7.2, which keeps the pH in the synaptic cleft relatively acidic. This inhibits the cone Ca²⁺ channels and consequently reduces the glutamate release by the cones. When horizontal cells hyperpolarize, the pannexin 1 channels decrease their conductance, the ATP release decreases, and the formation of the pH buffer reduces. The resulting alkalization in the synaptic cleft consequently increases cone glutamate release. Surprisingly, the hydrolysis of ATP instead of ATP itself mediates the synaptic modulation. Our results not only solve longstanding issues regarding horizontal cell to photoreceptor feedback, they also demonstrate a new form of synaptic modulation. Because pannexin 1 channels and ecto-ATPases are strongly expressed in the nervous system and pannexin 1 function is implicated in synaptic plasticity, we anticipate that this novel form of synaptic modulation may be a widespread phenomenon.

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How azide inhibits ATP hydrolysis by the F-ATPases.

Publications

How azide inhibits ATP hydrolysis by the F-ATPases.

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