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Regulation of hSos1 activity is a system-level property generated by its multi-domain structure

Paper ID Volume ID Publish Year Pages File Format Full-Text
14592 1232 2012 15 PDF Available
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 cdc25ts 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 aminoacid 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.

Keywords
hSos1; Ras-specific GEF; Inter-domain interactions; Intra-molecular regulation; Complementation of cdc25ts yeast; BIAcore; Stochastic mathematical model; Monte Carlo simulation; Sensitivity analysis
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Publisher
Database: Elsevier - ScienceDirect
Journal: Biotechnology Advances - Volume 30, Issue 1, January–February 2012, Pages 154–168
Authors
, , , , , , , , ,
Subjects
Physical Sciences and Engineering Chemical Engineering Bioengineering
Get Full-Text Now
Don't Miss Today's Special Offer
Price was $35.95
You save - $31
Price after discount Only $4.95
100% Money Back Guarantee
Full-text PDF Download
Online Support
Any Questions? feel free to contact us