Robust Signal Processing in Living Cells 英文参考文献.docVIP

RobustSignalProcessinginLivingCells RalfSteuer1,2*,SteffenWaldherr3,VictorSourjik4,MarkusKollmann5* 1InstituteforTheoreticalBiology,HumboldtUniversityofBerlin,Berlin,Germany,2ManchesterInterdisciplinaryBioCentre,TheUniversityofManchester,Manchester, United Kingdom, 3Universita¨t Stuttgart, Institute for Systems Theory and Automatic Control, Stuttgart, Germany, 4Zentrum fu¨r Molekulare Biologie der Universita¨t Heidelberg,DKFZ-ZMBHAlliance,Heidelberg,Germany,5Heinrich-Heine-Universita¨t Du¨sseldorf,DepartmentofBiology,Du¨sseldorf,Germany Abstract Cellular signaling networks have evolved an astonishing ability to function reliably and with high fidelity in uncertain environments.Acrucialprerequisiteforthehighprecisionexhibitedbymanysignalingcircuitsistheirabilitytokeepthe concentrationsofactivesignalingcompoundswithintightlydefinedbounds,despitestrongstochasticfluctuationsincopy numbersandotherdetrimentalinfluences.Basedonasimplemathematicalformalism,weidentifytopologicalorganizing principles that facilitate such robust control of intracellular concentrations in the face of multifarious perturbations. Our framework allows us to judge whether a multiple-input-multiple-output reaction network is robust against large perturbationsofnetworkparametersandenablesthepredictivedesignofperfectlyrobustsyntheticnetworkarchitectures. Utilizing the Escherichia coli chemotaxis pathway as a hallmark example, we provide experimental evidence that our frameworkindeedallowsustounravelthetopologicalorganizationofrobustsignaling.Wedemonstratethatthespecific organization of the pathway allows the system to maintain global concentration robustness of the diffusible response regulatorCheYwithrespecttoseveraldominantperturbations.Ourframeworkprovidesacounterpointtothehypothesis thatcellularfunctionreliesonanextensivemachinerytofine-tuneorcontrolintracellularparameters.Rather,wesuggest thatforalargeclassofperturbations,thereexistsanappropriatetopologythatrendersthenetworkoutputinvariantto