Trading the micro-world of combinatorial complexity for the macro-world of protein interaction domains.
Membrane receptors and proteins involved in signal transduction display numerous binding domains and operate as molecular scaffolds generating a variety of parallel reactions and protein complexes. The resulting combinatorial explosion of the number of feasible chemical species and, hence, different states of a network greatly impedes mechanistic modeling of signaling systems. Here we present novel general principles and identify kinetic requirements that allow us to replace a mechanistic picture of all possible micro-states and transitions by a macro-description of states of separate binding sites of network proteins. This domain-oriented approach dramatically reduces computational models of cellular signaling networks by dissecting mechanistic trajectories into the dynamics of macro- and meso-variables. We specify the conditions when the temporal dynamics of micro-states can be exactly or approximately expressed in terms of the product of the relative concentrations of separate domains. We prove that our macro-modeling approach equally applies to signaling systems with low population levels, analyzed by stochastic rather than deterministic equations. Thus, our results greatly facilitate quantitative analysis and computational modeling of multi-protein signaling networks.
Borisov
Nikolay M
NM
Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, 1020 Locust St., Philadelphia, PA 19107, USA.
Markevich
Nick I
NI
Hoek
Jan B
JB
Kholodenko
Boris N
BN
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D001665:Binding Sites; D002462:Cell Membrane / Q000378:metabolism*; D020650:Combinatorial Chemistry Techniques; D003198:Computer Simulation; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D008954:Models, Biological; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D008565:Membrane Proteins; D020794:Receptor Protein-Tyrosine Kinases