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Enriching the human apoptosis pathway by predicting the structures of protein-protein complexes.

ABSTRACT: Apoptosis is a matter of life and death for cells and both inhibited and enhanced apoptosis may be involved in the pathogenesis of human diseases. The structures of protein-protein complexes in the apoptosis signaling pathway are important as the structural pathway helps in understanding the mechanism of the regulation and information transfer, and in identifying targets for drug design. Here, we aim to predict the structures toward a more informative pathway than currently available. Based on the 3D structures of complexes in the target pathway and a protein-protein interaction modeling tool which allows accurate and proteome-scale applications, we modeled the structures of 29 interactions, 21 of which were previously unknown. Next, 27 interactions which were not listed in the KEGG apoptosis pathway were predicted and subsequently validated by the experimental data in the literature. Additional interactions are also predicted. The multi-partner hub proteins are analyzed and interactions that can and cannot co-exist are identified. Overall, our results enrich the understanding of the pathway with interactions and provide structural details for the human apoptosis pathway. They also illustrate that computational modeling of protein-protein interactions on a large scale can help validate experimental data and provide accurate, structural atom-level detail of signaling pathways in the human cell.

SUBMITTER: Acuner Ozbabacan SE

PROVIDER: S-EPMC3378801 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Enriching the human apoptosis pathway by predicting the structures of protein-protein complexes.

Acuner Ozbabacan Saliha Ece SE Keskin Ozlem O Nussinov Ruth R Gursoy Attila A

Journal of structural biology 20120214 3

Apoptosis is a matter of life and death for cells and both inhibited and enhanced apoptosis may be involved in the pathogenesis of human diseases. The structures of protein-protein complexes in the apoptosis signaling pathway are important as the structural pathway helps in understanding the mechanism of the regulation and information transfer, and in identifying targets for drug design. Here, we aim to predict the structures toward a more informative pathway than currently available. Based on t ...[more]

PMID: 22349545

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Project description:Electron transfer reactions are essential for life because they underpin oxidative phosphorylation and photosynthesis, processes leading to the generation of ATP, and are involved in many reactions of intermediary metabolism. Key to these roles is the formation of transient inter-protein electron transfer complexes. The structural basis for the control of specificity between partner proteins is lacking because these weak transient complexes have remained largely intractable for crystallographic studies. Inter-protein electron transfer processes are central to all of the key steps of denitrification, an alternative form of respiration in which bacteria reduce nitrate or nitrite to N2 through the gaseous intermediates nitric oxide (NO) and nitrous oxide (N2O) when oxygen concentrations are limiting. The one-electron reduction of nitrite to NO, a precursor to N2O, is performed by either a haem- or copper-containing nitrite reductase (CuNiR) where they receive an electron from redox partner proteins a cupredoxin or a c-type cytochrome. Here we report the structures of the newly characterized three-domain haem-c-Cu nitrite reductase from Ralstonia pickettii (RpNiR) at 1.01 Å resolution and its M92A and P93A mutants. Very high resolution provides the first view of the atomic detail of the interface between the core trimeric cupredoxin structure of CuNiR and the tethered cytochrome c domain that allows the enzyme to function as an effective self-electron transfer system where the donor and acceptor proteins are fused together by genomic acquisition for functional advantage. Comparison of RpNiR with the binary complex of a CuNiR with a donor protein, AxNiR-cytc551 (ref. 6), and mutagenesis studies provide direct evidence for the importance of a hydrogen-bonded water at the interface in electron transfer. The structure also provides an explanation for the preferential binding of nitrite to the reduced copper ion at the active site in RpNiR, in contrast to other CuNiRs where reductive inactivation occurs, preventing substrate binding.

Dataset Information

Enriching the human apoptosis pathway by predicting the structures of protein-protein complexes.

Publications

Enriching the human apoptosis pathway by predicting the structures of protein-protein complexes.

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