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Design principles of nuclear receptor signaling: how complex networking improves signal transduction

Kolodkin, AN, Bruggeman, FJ, Plant, N, Mone, MJ, Bakker, BM, Campbell, MJ, van Leeuwen, JPTM, Carlberg, C, Snoep, JL and Westerhoff, HV (2010) Design principles of nuclear receptor signaling: how complex networking improves signal transduction Molecular Systems Biology, 6. ISSN 1744-4292

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Abstract

The topology of nuclear receptor (NR) signaling is captured in a systems biological graphical notation. This enables us to identify a number of 'design' aspects of the topology of these networks that might appear unnecessarily complex or even functionally paradoxical. In realistic kinetic models of increasing complexity, calculations show how these features correspond to potentially important design principles, e.g.: (i) cytosolic 'nuclear' receptor may shuttle signal molecules to the nucleus, (ii) the active export of NRs may ensure that there is sufficient receptor protein to capture ligand at the cytoplasmic membrane, (iii) a three conveyor belts design dissipating GTP-free energy, greatly aids response, (iv) the active export of importins may prevent sequestration of NRs by importins in the nucleus and (v) the unspecific nature of the nuclear pore may ensure signal-flux robustness. In addition, the models developed are suitable for implementation in specific cases of NR-mediated signaling, to predict individual receptor functions and differential sensitivity toward physiological and pharmacological ligands. Molecular Systems Biology 6: 446; published online 21 December 2010; doi:10.1038/msb.2010.102

Item Type: Article
Uncontrolled Keywords: biochemical network, kinetic model, nuclear receptor, signaling, systems biology, LIGAND-BINDING DOMAIN, GENERALIZED GLUCOCORTICOID RESISTANCE, STEROID-RECEPTORS, RESPONSE ELEMENT, THYROID-HORMONE, IMPORTIN-ALPHA, POINT MUTATION, LIVING CELLS, PROTEIN, TRANSLOCATION
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Divisions: Faculty of Health and Medical Sciences > Biochemistry and Physiology
Depositing User: Symplectic Elements
Date Deposited: 25 May 2011 10:02
Last Modified: 08 Nov 2013 12:07
URI: http://epubs.surrey.ac.uk/id/eprint/2865

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