Surviving heat shock: Control strategies for robustness and performance

Abstract

Molecular biology studies the cause-and-effect relationships among microscopic processes initiated by individual molecules within a cell and observes their macroscopic phenotypic effects on cells and organisms. These studies provide a wealth of information about the underlying networks and pathways responsible for the basic functionality and robustness of biological systems. At the same time, these studies create exciting opportunities for the development of quantitative and predictive models that connect the mechanism to its phenotype then examine various modular structures and the range of their dynamical behavior. The use of such models enables a deeper understanding of the design principles underlying biological organization and makes their reverse engineering and manipulation both possible and tractable The heat shock response presents an interesting mechanism where such an endeavor is possible. Using a model of heat shock, we extract the design motifs in the system and justify their existence in terms of various performance objectives. We also offer a modular decomposition that parallels that of traditional engineering control architectures.control theory ͉ heat shock stress response ͉ mathematical modeling A systems approach is a promising venue for studying biological complexity. The hallmark of this approach is an analysis of the dynamics of the biological network and the protocols used for their interactions. Experiences from fields like engineering, where model-based analysis and design have been the central paradigm, provide a glimpse of what is achievable (1). Biology and engineering share many similarities at the system level (2), including the use of complexity to achieve robustness and performance rather than for minimal functionality. We define robustness as the capability of a system to operate reliably when its physical parameters vary within their expected ranges; conversely, fragility is defined as hypersensitivity to such parametric variations. We suspect that the comparative study of genetic networks will confirm that robustness and the ability to achieve prompt adaptation in the presence of environmental challenges impose severe constraints on the underlying architecture of a system and are the source of the general design motifs repeated in many cellular networks.Here, we study the heat shock response (hsr) in Escherichia coli. The hsr is universally conserved among organisms and serves to remedy protein damage induced by heat and other stresses (reviewed in ref.3). We build a model for the E. coli hsr system, analyze its layers of regulation, and argue that its complexity is a necessary outcome of design requirements such as robustness, speed of response, noise rejection, and efficiency. This model provides useful insight into the heat shock system design architecture. It also suggests a mathematical and conceptual modular decomposition that defines the functional blocks or submodules of the heat shock system. This decomposition is drawn by analogy to manmade control systems and is foun...

Computational Heuristics for Simplifying a Biological Model

“…There is however a crucial difference which points to their significance for the model: when increasing the initial level of hsf 3 , even in such a way that the total level of hsf is unchanged, the fit to the DNA binding experimental data of [7] is drastically changed.…”

“…First, as a well-conserved mechanism in all eukaryotes, it is considered a promising candidate for investigating the engineering principles of gene regulatory networks, see [3,4,8,18]. Second, heat shock proteins (hsp) act as main components in a large number of cellular processes such as signaling, regulation and inflammation, see [6,16].…”

GroEL to DnaK chaperone network behind the stability modulation of σ32 at physiological temperature in Escherichia coli

“…The cellular level of r 32 (10-30 copies/cell) increases by 12-15-fold upon shifting the cells from physiological temperature (30°C) to a heat-stress one (45°C), with transient induction of chaperones and proteases [7][8][9][10][11]. However, over-expression of r 32 is toxic to the cells [12].…”

“…At physiological temperature, alterations of protein conformation occur also as a consequence of different environmental stresses other than heat. Thus, tight regulation of the expression of chaperones and proteases are crucial to maintain the cellular protein folding environment at physiological as well as under a number of stressed conditions [7][8][9].…”

“…However, over-expression of r 32 is toxic to the cells [12]. A complex negative feedback pathway is known to regulate tightly the cellular level of r 32 by its own transcribed gene products viz., DnaK chaperone system and FtsH protease [7][8][9][12][13][14][15][16]. The existing model for regulation of r 32 stability is the 'protein titration model', that depicts unfolded proteins and r 32 competing for binding with DnaK; accumulation of unfolded proteins relative to the basal level titrates away DnaK from r 32 and consequently r 32 becomes stable and active, resulting in overproduction of DnaK, which binds free r 32 to make the r 32 accessible to FtsH attack and thereby r 32 becomes further unstable [7,8,12,15,16].…”