Structural Data in Synthetic Biology Approaches for Studying General Design Principles of Cellular Signaling Networks

Kiel, Christina; Serrano, Luís

doi:10.1016/j.str.2012.10.002

Cited by 14 publications

(8 citation statements)

References 67 publications

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“…The importance of combining structural data in functional protein network analysis has been recently highlighted (Kiel et al, 2011). Our results will pave the way to the construction of dynamic mathematical model(s) of increasing granularity, as well as to mutational and synthetic biology approaches (Kiel and Serrano, 2012) able to proof novel regulatory links within the Whi5 network.…”

Section: Discussionmentioning

confidence: 87%

A comparative study of Whi5 and retinoblastoma proteins: from sequence and structure analysis to intracellular networks

et al. 2014

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Cell growth and proliferation require a complex series of tight-regulated and well-orchestrated events. Accordingly, proteins governing such events are evolutionary conserved, even among distant organisms. By contrast, it is more singular the case of “core functions” exerted by functional analogous proteins that are not homologous and do not share any kind of structural similarity. This is the case of proteins regulating the G1/S transition in higher eukaryotes–i.e., the retinoblastoma (Rb) tumor suppressor Rb—and budding yeast, i.e., Whi5. The interaction landscape of Rb and Whi5 is quite large, with more than one hundred proteins interacting either genetically or physically with each protein. The Whi5 interactome has been used to construct a concept map of Whi5 function and regulation. Comparison of physical and genetic interactors of Rb and Whi5 allows highlighting a significant core of conserved, common functionalities associated with the interactors indicating that structure and function of the network—rather than individual proteins—are conserved during evolution. A combined bioinformatics and biochemical approach has shown that the whole Whi5 protein is highly disordered, except for a small region containing the protein family signature. The comparison with Whi5 homologs from Saccharomycetales has prompted the hypothesis of a modular organization of structural disorder, with most evolutionary conserved regions alternating with highly variable ones. The finding of a consensus sequence points to the conservation of a specific phosphorylation rhythm along with two disordered sequence motifs, probably acting as phosphorylation-dependent seeds in Whi5 folding/unfolding. Thus, the widely disordered Whi5 appears to act as a hierarchical, “date hub” that has evolutionary assayed an original way of modular organization before being supplanted by the globular, multi-domain structured Rb, more suitable to cover the role of a “party hub”.

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Section: Discussionmentioning

confidence: 87%

A comparative study of Whi5 and retinoblastoma proteins: from sequence and structure analysis to intracellular networks

et al. 2014

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“…This property gives rise to the idea that “everything regulates everything else” and fuels the question of what mechanisms cells have evolved to selectively activate particular signaling molecules and pathways (Kiel and Serrano, 2012b), without inevitably having broad pleiotropic effects on the entire signaling architecture (Granek et al, 2011; Guruharsha et al, 2012; Kiel and Serrano, 2012a). …”

Section: Signaling Network Are Highly Interconnectedmentioning

confidence: 99%

Disentangling biological signaling networks by dynamic coupling of signaling lipids to modifying enzymes

Blind

2014

Advances in Biological Regulation

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An unresolved problem in biological signal transduction is how particular branches of highly interconnected signaling networks can be decoupled, allowing activation of specific circuits within complex signaling architectures. Although signaling dynamics and spatiotemporal mechanisms serve critical roles, it remains unclear if these are the only ways cells achieve specificity within networks. The transcription factor Steroidogenic Factor-1 (SF-1) is an excellent model to address this question, as it forms dynamic complexes with several chemically distinct lipid species (phosphatidylinositols, phosphatidylcholines and sphingolipids). This property is important since lipids bound to SF-1 are modified by lipid signaling enzymes (IPMK & PTEN), regulating SF-1 biological activity in gene expression. Thus, a particular SF-1/lipid complex can interface with a lipid signaling enzyme only if SF-1 has been loaded with a chemically compatible lipid substrate. This mechanism permits dynamic downstream responsiveness to constant upstream input, disentangling specific pathways from the full network. The potential of this paradigm to apply generally to nuclear lipid signaling is discussed, with particular attention given to the nuclear receptor superfamily of transcription factors and their phospholipid ligands.

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“…However, in spite of this importance, the rate at which the structures of protein complexes are being solved experimentally lags far behind the rate at which interactions are being discovered. As such, there is a pressing need to fill this ever-growing gap with models derived through computational means such as docking [38-45] and post-docking analysis [46,47]. …”

Section: Introductionmentioning

confidence: 99%

The scoring of poses in protein-protein docking: current capabilities and future directions

et al. 2013

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BackgroundProtein-protein docking, which aims to predict the structure of a protein-protein complex from its unbound components, remains an unresolved challenge in structural bioinformatics. An important step is the ranking of docked poses using a scoring function, for which many methods have been developed. There is a need to explore the differences and commonalities of these methods with each other, as well as with functions developed in the fields of molecular dynamics and homology modelling.ResultsWe present an evaluation of 115 scoring functions on an unbound docking decoy benchmark covering 118 complexes for which a near-native solution can be found, yielding top 10 success rates of up to 58%. Hierarchical clustering is performed, so as to group together functions which identify near-natives in similar subsets of complexes. Three set theoretic approaches are used to identify pairs of scoring functions capable of correctly scoring different complexes. This shows that functions in different clusters capture different aspects of binding and are likely to work together synergistically.ConclusionsAll functions designed specifically for docking perform well, indicating that functions are transferable between sampling methods. We also identify promising methods from the field of homology modelling. Further, differential success rates by docking difficulty and solution quality suggest a need for flexibility-dependent scoring. Investigating pairs of scoring functions, the set theoretic measures identify known scoring strategies as well as a number of novel approaches, indicating promising augmentations of traditional scoring methods. Such augmentation and parameter combination strategies are discussed in the context of the learning-to-rank paradigm.

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Structural Data in Synthetic Biology Approaches for Studying General Design Principles of Cellular Signaling Networks

Cited by 14 publications

References 67 publications

A comparative study of Whi5 and retinoblastoma proteins: from sequence and structure analysis to intracellular networks

A comparative study of Whi5 and retinoblastoma proteins: from sequence and structure analysis to intracellular networks

Disentangling biological signaling networks by dynamic coupling of signaling lipids to modifying enzymes

The scoring of poses in protein-protein docking: current capabilities and future directions

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