title: Regulation of hSos1 activity is a system-level property generated by its multi-domain structure.
abstract: The multi-domain protein hSos1 plays a major role in cell growth and differentiation through its Ras-specific guanine nucleotide exchange domain whose complex regulation involves intra-molecular, inter-domain rearrangements. We present a stochastic mathematical model describing intra-molecular regulation of hSos1 activity. The population macroscopic effect is reproduced through a Monte-Carlo approach. Key model parameters have been experimentally determined by BIAcore analysis. Complementation experiments of a Saccharomyces cerevisiae cdc25(ts) strain with Sos deletion mutants provided a comprehensive data set for estimation of unknown parameters and model validation. The model is robust against parameter alteration and describes both the behavior of Sos deletion mutants and modulation of activity of the full length molecule under physiological conditions. By incorporating the calculated effect of amino acid changes at an inter-domain interface, the behavior of a mutant correlating with a developmental syndrome could be simulated, further validating the model. The activation state of Ras-specific guanine nucleotide exchange domain of hSos1 arises as an "emergent property" of its multi-domain structure that allows multi-level integration of a complex network of intra- and inter-molecular signals.
authors.affiliation: Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milano, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Sacco
authors.forename: Marcello
authors.initials: M
authors.lastname: Farina
authors.forename: Claudio
authors.initials: C
authors.lastname: Greco
authors.forename: Stefano
authors.initials: S
authors.lastname: Lamperti
authors.forename: Stefano
authors.initials: S
authors.lastname: Busti
authors.forename: Luca
authors.initials: L
authors.lastname: Degioia
authors.forename: Lilia
authors.initials: L
authors.lastname: Alberghina
authors.forename: Diego
authors.initials: D
authors.lastname: Liberati
authors.forename: Marco
authors.initials: M
authors.lastname: Vanoni
mesh_terms: D019295:Computational Biology; D055786:Gene Knockout Techniques; D005816:Genetic Complementation Test; D006801:Humans; D008957:Models, Genetic; D008958:Models, Molecular; D009010:Monte Carlo Method; D054730:Protein Interaction Domains and Motifs; D017434:Protein Structure, Tertiary; D020837:SOS1 Protein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D020798:Two-Hybrid System Techniques; D020663:ras Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D020837:SOS1 Protein; D020663:ras Guanine Nucleotide Exchange Factors