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His26 protonation in cytochrome c triggers microsecond ?-sheet formation and heme exposure: implications for apoptosis.

ABSTRACT: Cytochrome c unfolds locally and reversibly upon heating at pH 3. UV resonance Raman (UVRR) spectra reveal that instead of producing unordered structure, unfolding converts turns and some helical elements to ?-sheet. It also disrupts the Met80-heme bond, and has been previously shown to induce peroxidase activity. Aromatic residues that are H-bonded to a heme propionate (Trp59 and Tyr48) alter their orientation, indicating heme displacement. T-jump/UVRR measurements give time constants of 0.2, 3.9, and 67 ?s for successive phases of ?-sheet formation and concomitant reorientation of Trp59. UVRR spectra reveal protonation of histidines, and specifically of His26, whose H-bond to Pro44 anchors the 40s ? loop; this loop is known to be the least stable 'foldon' in the protein. His26 protonation is proposed to disrupt its H-bond with Pro44, triggering the extension of a short ?-sheet segment at the 'neck' of the 40s ? loop into the loop itself and back into the 60s and 70s helices. The secondary structure change displaces the heme via H-bonds from residues in the growing ?-sheet, thereby exposing it to exogenous ligands, and inducing peroxidase activity. This unfolding mechanism may play a role in cardiolipin peroxidation by cyt c during apoptosis.

SUBMITTER: Balakrishnan G

PROVIDER: S-EPMC3529097 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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His26 protonation in cytochrome c triggers microsecond β-sheet formation and heme exposure: implications for apoptosis.

Balakrishnan Gurusamy G Hu Ying Y Spiro Thomas G TG

Journal of the American Chemical Society 20121106 46

Cytochrome c unfolds locally and reversibly upon heating at pH 3. UV resonance Raman (UVRR) spectra reveal that instead of producing unordered structure, unfolding converts turns and some helical elements to β-sheet. It also disrupts the Met80-heme bond, and has been previously shown to induce peroxidase activity. Aromatic residues that are H-bonded to a heme propionate (Trp59 and Tyr48) alter their orientation, indicating heme displacement. T-jump/UVRR measurements give time constants of 0.2, 3 ...[more]

PMID: 23094892

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Project description:Membrane cytochrome b5 reductase is a pleiotropic oxidoreductase that uses primarily soluble reduced nicotinamide adenine dinucleotide (NADH) as an electron donor to reduce multiple biological acceptors localized in cellular membranes. Some of the biological acceptors of the reductase and coupled redox proteins might eventually transfer electrons to oxygen to form reactive oxygen species. Additionally, an inefficient electron transfer to redox acceptors can lead to electron uncoupling and superoxide anion formation by the reductase. Many efforts have been made to characterize the involved catalytic domains in the electron transfer from the reduced flavoprotein to its electron acceptors, such as cytochrome b5, through a detailed description of the flavin and NADH-binding sites. This information might help to understand better the processes and modifications involved in reactive oxygen formation by the cytochrome b5 reductase. Nevertheless, more than half a century since this enzyme was first purified, the one-electron transfer process toward potential electron acceptors of the reductase is still only partially understood. New advances in computational analysis of protein structures allow predicting the intramolecular protein dynamics, identifying potential functional sites, or evaluating the effects of microenvironment changes in protein structure and dynamics. We applied this approach to characterize further the roles of amino acid domains within cytochrome b5 reductase structure, part of the catalytic domain, and several sensors and structural domains involved in the interactions with cytochrome b5 and other electron acceptors. The computational analysis results allowed us to rationalize some of the available spectroscopic data regarding ligand-induced conformational changes leading to an increase in the flavin adenine dinucleotide (FAD) solvent-exposed surface, which has been previously correlated with the formation of complexes with electron acceptors.

Dataset Information

His26 protonation in cytochrome c triggers microsecond ?-sheet formation and heme exposure: implications for apoptosis.

Publications

His26 protonation in cytochrome c triggers microsecond β-sheet formation and heme exposure: implications for apoptosis.

Similar Datasets

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