AI Article Synopsis

  • Mitochondrial cytochrome c (Cyt c) not only facilitates electron transfer but also plays a critical role in apoptosis, with its activity influenced by nitrosylation and the cleavage of the Fe-Met80 bond.
  • Nitrosylation affects the heme structure of Cyt c, causing significant conformational changes depending on whether the iron is in a ferrous or ferric state, impacting its peroxidase activity.
  • Time-resolved studies show that the binding and dissociation of nitric oxide (NO) from Cyt c occur rapidly, with subsequent Met80 rebinding being much slower, highlighting the intricate dynamics involved in Cyt c's function and its implications for apoptosis.

Article Abstract

Apart from its role in electron transfer, mitochondrial cytochrome c also plays a role in apoptosis and is subject to nitrosylation. The cleavage of the Fe-Met80 bond plays a role in several processes including the release of Cyt c from mitochondria or increase of its peroxidase activity. Nitrosylation of Cyt c precludes the reformation of the disrupted Fe-Met80 bond and was shown to occur during apoptosis. These physiological properties are associated with a conformational change of the heme center of Cyt c. Here, we demonstrate that NO binding induces pronounced heme conformational changes in the six-coordinate Cyt c-NO complex. Equilibrium and time-resolved Raman data reveal that the heme structural conformation depends both on the nature of the distal iron ligand (NO or Met80) and on the Fe or Fe heme redox state. Upon nitrosylation, the heme ruffling distortion is greatly enhanced for ferrous Cyt c. Contrastingly, the initial strong heme distortion in native ferric Cyt c almost disappears after NO binding. We measured the heme coordination dynamics in the picosecond to second time range and identified Met80 and NO rebinding phases using time-resolved Raman and absorption spectroscopies. Dissociation of NO instantly produces 5-coordinate heme with a domed structure which continues to rearrange within 15 ps, while the initial ruffling distortion disappears. The rates of Cyt c-NO complex formation measured by transient absorption are k = 1.81 × 10 M s for ferric Cyt c and 83 M s for ferrous Cyt c. After NO dissociation and exit from the heme pocket, the rebinding of Met80 to the heme iron takes place 6 orders of magnitude more slowly (3-5 μs) than Met80 rebinding in the absence of NO (5 ps). Altogether, these data reveal the structural and dynamic properties of Cyt c in interaction with nitric oxide relevant for the molecular mechanism of apoptosis.

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Source
http://dx.doi.org/10.1039/c7cp02634jDOI Listing

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