An engineered protein-phosphorylation toggle network with implications for endogenous network discovery

Science ◽  
2021 ◽  
Vol 373 (6550) ◽  
pp. eaav0780
Author(s):  
Deepak Mishra ◽  
Tristan Bepler ◽  
Brian Teague ◽  
Bonnie Berger ◽  
Jim Broach ◽  
...  
Keyword(s):  
Protein Phosphorylation ◽  
Biological Networks ◽  
Toggle Switch ◽  
Computational Framework ◽  
Cellular Processes ◽  
Network Discovery ◽  
Endogenous Protein ◽  
Synthetic Protein ◽  
Endogenous Networks ◽  
Cellular Behaviors

Synthetic biological networks comprising fast, reversible reactions could enable engineering of new cellular behaviors that are not possible with slower regulation. Here, we created a bistable toggle switch in Saccharomyces cerevisiae using a cross-repression topology comprising 11 protein-protein phosphorylation elements. The toggle is ultrasensitive, can be induced to switch states in seconds, and exhibits long-term bistability. Motivated by our toggle’s architecture and size, we developed a computational framework to search endogenous protein pathways for other large and similar bistable networks. Our framework helped us to identify and experimentally verify five formerly unreported endogenous networks that exhibit bistability. Building synthetic protein-protein networks will enable bioengineers to design fast sensing and processing systems, allow sophisticated regulation of cellular processes, and aid discovery of endogenous networks with particular functions.

scholarly journals Structural Insights into Protein Regulation by Phosphorylation and Substrate Recognition of Protein Kinases/Phosphatases

Life ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 957
Author(s):  
Seung-Hyeon Seok
Keyword(s):  
Protein Phosphorylation ◽  
Protein Kinases ◽  
Protein Phosphatases ◽  
Substrate Recognition ◽  
Protein Structures ◽  
Phosphate Group ◽  
Amino Acid Side Chain ◽  
Post Translational Modification ◽  
Cellular Processes ◽  
Structural Insights

Protein phosphorylation is one of the most widely observed and important post-translational modification (PTM) processes. Protein phosphorylation is regulated by protein kinases, each of which covalently attaches a phosphate group to an amino acid side chain on a serine (Ser), threonine (Thr), or tyrosine (Tyr) residue of a protein, and by protein phosphatases, each of which, conversely, removes a phosphate group from a phosphoprotein. These reversible enzyme activities provide a regulatory mechanism by activating or deactivating many diverse functions of proteins in various cellular processes. In this review, their structures and substrate recognition are described and summarized, focusing on Ser/Thr protein kinases and protein Ser/Thr phosphatases, and the regulation of protein structures by phosphorylation. The studies reviewed here and the resulting information could contribute to further structural, biochemical, and combined studies on the mechanisms of protein phosphorylation and to drug discovery approaches targeting protein kinases or protein phosphatases.

An algebraic approach to parameter optimization in biomolecular bistable systems

2016 ◽  
Author(s):  
Vahid Mardanlou ◽  
Elisa Franco
Keyword(s):  
Parameter Optimization ◽  
Biological Networks ◽  
Optimization Problem ◽  
Biological Network ◽  
Algebraic Approach ◽  
Reaction Rates ◽  
Toggle Switch ◽  
Switching Speed ◽  
Bistable Systems ◽  
Total Concentrations

AbstractIn a synthetic biological network it may often be desirable to maximize or minimize parameters such as reaction rates, fluxes and total concentrations of reagents, while preserving a given dynamic behavior. We consider the problem of parameter optimization in biomolecular bistable circuits. We show that, under some assumptions often satisfied by bistable biological networks, it is possible to derive algebraic conditions on the parameters that determine when bistability occurs. These (global) algebraic conditions can be included as nonlinear constraints in a parameter optimization problem. We derive bistability conditions using Sturm's theorem for Gardner and Collins toggle switch. Then we optimize its nominal parameters to improve switching speed and robustness to a subset of uncertain parameters.

Endogenous protein phosphorylation and casein kinase activity during seed development in Araucaria angustifolia

2002 ◽  
Vol 61 (7) ◽  
pp. 835-842 ◽  
Author(s):  
Edna Lôbo Machado ◽  
Alba Chiesse da Silva ◽  
Márcio J da Silva ◽  
Adilson Leite ◽  
Laura M.M Ottoboni
Keyword(s):  
Protein Phosphorylation ◽  
Seed Development ◽  
Kinase Activity ◽  
Casein Kinase ◽  
Araucaria Angustifolia ◽  
Endogenous Protein

scholarly journals Hormone-induced protein phosphorylation. I. Relationship between secretagogue action and endogenous protein phosphorylation in intact cells from the exocrine pancreas and parotid.

1982 ◽  
Vol 95 (3) ◽  
pp. 903-908 ◽  
Author(s):  
S D Freedman ◽  
J D Jamieson
Keyword(s):  
Protein Phosphorylation ◽  
Exocrine Pancreas ◽  
Second Messengers ◽  
Intact Cells ◽  
Cholecystokinin Octapeptide ◽  
Phosphorylation Of Proteins ◽  
Endogenous Protein ◽  
Dose Dependent Fashion ◽  
Dose Dependent

We undertook studies to determine whether secretagogue action on the exocrine pancreas and parotid is accompanied by phosphorylation of proteins in intact cells. For this purpose, rat pancreatic, and parotid lobules were preincubated with 32Pi for 45 min at 37 degrees C, washed, and then incubated at 37 degrees C in the presence or absence of secretagogues that effect discharge through different second messengers. Among a variety of polypeptides exhibiting enhanced phosphorylation in pancreatic lobules upon a 30-s incubation in the presence of the secretagogues carbamylcholine, cholecystokinin octapeptide, or secretin, one species with an Mr of 29,000 was especially notable for three reasons: (a) its enhanced level of phosphorylation was dependent on the dose of secretagogue used and was still apparent after incubation for 30 min at 37 degrees C; (b) an analogous phosphorylated polypeptide was observed in isoproterenol-stimulated parotid lobules; and (c) in both tissues its selective dephosphorylation was observed upon termination of stimulation by administration of atropine to carbamylcholine-stimulated pancreatic lobules and propranolol to isoproterenol-stimulated parotid lobules. These results suggest that the phosphorylation of one protein with an Mr of 29,000 is closely correlated both temporally and in a dose-dependent fashion with secretagogue action in both the exocrine pancreas and parotid.

scholarly journals Application of an Integrative Computational Framework in Trancriptomic Data of Atherosclerotic Mice Suggests Numerous Molecular Players

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Olga Papadodima ◽  
Allan Sirsjö ◽  
Fragiskos N. Kolisis ◽  
Aristotelis Chatziioannou
Keyword(s):  
Cell Communication ◽  
Computational Framework ◽  
Bioinformatic Tools ◽  
Cellular Processes ◽  
Similar Expression Profile ◽  
Apoe Knockout Mice ◽  
Cellular Pathways ◽  
Functional Relevance ◽  
Atherosclerosis Research ◽  
Molecular Description

Atherosclerosis is a multifactorial disease involving a lot of genes and proteins recruited throughout its manifestation. The present study aims to exploit bioinformatic tools in order to analyze microarray data of atherosclerotic aortic lesions of ApoE knockout mice, a model widely used in atherosclerosis research. In particular, a dynamic analysis was performed among young and aged animals, resulting in a list of 852 significantly altered genes. Pathway analysis indicated alterations in critical cellular processes related to cell communication and signal transduction, immune response, lipid transport, and metabolism. Cluster analysis partitioned the significantly differentiated genes in three major clusters of similar expression profile. Promoter analysis applied to functional related groups of the same cluster revealed shared putative cis-elements potentially contributing to a common regulatory mechanism. Finally, by reverse engineering the functional relevance of differentially expressed genes with specific cellular pathways, putative genes acting as hubs, were identified, linking functionally disparate cellular processes in the context of traditional molecular description.

CAN COMPLEX CELLULAR PROCESSES BE GOVERNED BY SIMPLE LINEAR RULES?

2009 ◽  
Vol 07 (01) ◽  
pp. 243-268 ◽  
Author(s):  
KUMAR SELVARAJOO ◽  
MASARU TOMITA ◽  
MASA TSUCHIYA
Keyword(s):  
Biological Networks ◽  
Biological Network ◽  
Living Systems ◽  
Regulatory Motifs ◽  
Cellular Processes ◽  
Self Organized ◽  
Wide Range ◽  
Activation Response ◽  
Physical Reasons

Complex living systems have shown remarkably well-orchestrated, self-organized, robust, and stable behavior under a wide range of perturbations. However, despite the recent generation of high-throughput experimental datasets, basic cellular processes such as division, differentiation, and apoptosis still remain elusive. One of the key reasons is the lack of understanding of the governing principles of complex living systems. Here, we have reviewed the success of perturbation–response approaches, where without the requirement of detailed in vivo physiological parameters, the analysis of temporal concentration or activation response unravels biological network features such as causal relationships of reactant species, regulatory motifs, etc. Our review shows that simple linear rules govern the response behavior of biological networks in an ensemble of cells. It is daunting to know why such simplicity could hold in a complex heterogeneous environment. Provided physical reasons can be explained for these phenomena, major advancement in the understanding of basic cellular processes could be achieved.

scholarly journals Dissecting molecular network structures using a network subgraph approach

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e9556
Author(s):  
Chien-Hung Huang ◽  
Efendi Zaenudin ◽  
Jeffrey J.P. Tsai ◽  
Nilubon Kurubanjerdjit ◽  
Eskezeia Y. Dessie ◽  
...  
Keyword(s):  
Biological Networks ◽  
Spectral Graph Theory ◽  
Molecular Networks ◽  
Driver Genes ◽  
Complexity Measures ◽  
Cellular Processes ◽  
Graph Energy ◽  
Energy Cutoff ◽  
Cancer Networks ◽  
Irreducible Graphs

Biological processes are based on molecular networks, which exhibit biological functions through interactions of genetic elements or proteins. This study presents a graph-based method to characterize molecular networks by decomposing the networks into directed multigraphs: network subgraphs. Spectral graph theory, reciprocity and complexity measures were used to quantify the network subgraphs. Graph energy, reciprocity and cyclomatic complexity can optimally specify network subgraphs with some degree of degeneracy. Seventy-one molecular networks were analyzed from three network types: cancer networks, signal transduction networks, and cellular processes. Molecular networks are built from a finite number of subgraph patterns and subgraphs with large graph energies are not present, which implies a graph energy cutoff. In addition, certain subgraph patterns are absent from the three network types. Thus, the Shannon entropy of the subgraph frequency distribution is not maximal. Furthermore, frequently-observed subgraphs are irreducible graphs. These novel findings warrant further investigation and may lead to important applications. Finally, we observed that cancer-related cellular processes are enriched with subgraph-associated driver genes. Our study provides a systematic approach for dissecting biological networks and supports the conclusion that there are organizational principles underlying molecular networks.

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