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Signaling through receptors and scaffolds: independent interactions reduce combinatorial complexity.

ABSTRACT: After activation, many receptors and their adaptor proteins act as scaffolds displaying numerous docking sites and engaging multiple targets. The consequent assemblage of a variety of protein complexes results in a combinatorial increase in the number of feasible molecular species presenting different states of a receptor-scaffold signaling module. Tens of thousands of such microstates emerge even for the initial signal propagation events, greatly impeding a quantitative analysis of networks. Here, we demonstrate that the assumption of independence of molecular events occurring at distinct sites enables us to approximate a mechanistic picture of all possible microstates by a macrodescription of states of separate domains, i.e., macrostates that correspond to experimentally verifiable variables. This analysis dissects a highly branched network into interacting pathways originated by protein complexes assembled on different sites of receptors and scaffolds. We specify when the temporal dynamics of any given microstate can be expressed using the product of the relative concentrations of individual sites. The methods presented here are equally applicable to deterministic and stochastic calculations of the temporal dynamics. Our domain-oriented approach drastically reduces the number of states, processes, and kinetic parameters to be considered for quantification of complex signaling networks that propagate distinct physiological responses.

SUBMITTER: Borisov NM

PROVIDER: S-EPMC1366644 | biostudies-literature | 2005 Aug

REPOSITORIES: biostudies-literature

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Signaling through receptors and scaffolds: independent interactions reduce combinatorial complexity.

Borisov Nikolay M NM Markevich Nick I NI Hoek Jan B JB Kholodenko Boris N BN

Biophysical journal 20050527 2

After activation, many receptors and their adaptor proteins act as scaffolds displaying numerous docking sites and engaging multiple targets. The consequent assemblage of a variety of protein complexes results in a combinatorial increase in the number of feasible molecular species presenting different states of a receptor-scaffold signaling module. Tens of thousands of such microstates emerge even for the initial signal propagation events, greatly impeding a quantitative analysis of networks. He ...[more]

PMID: 15923229

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Signaling through receptors and scaffolds: independent interactions reduce combinatorial complexity.

Publications

Signaling through receptors and scaffolds: independent interactions reduce combinatorial complexity.

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