Understanding the Dynamics of Biological Systems Lessons Learned fro
Systems biology has risen as a direct result of the limitation of conventional (reductionistic) biology to understand complex phenomena emerging as a result of dynamic and multiscale biological interactions. By applying mathematical and computational mode
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Effects of Protein Quality Control Machinery on Protein Homeostasis Conner I. Sandefur and Santiago Schnell
1.1 Protein Folding is Catalyzed by a Complex Network of Reactions A driving force of systems biology is the desire to understand the many interactions that compose the pathways within a cell. Systems biology is interested in the interactions and emergent properties that result from communication between different system components. Reducing a system (e.g., a cell) to its parts (e.g., individual genes and proteins) neglects component interaction and emergent properties. Building and investigating a complete interaction map provides insight into normal and diseased individuals that might not be found by traditional methods. Much of traditional biology has the central dogma of molecular biology at its basis. This dogma states that DNA is transcribed into RNA which is translated into protein (Crick 1970), and has guided the study of individual genes and the proteins they encode. The protein folding network provides an example of how the central dogma of molecular biology does not explain many of the interactions within cells. DNA transcription is initiated by proteins and is the first step in protein production. For a number of eukaryotic proteins, the process continues with co-translation through ribosomes into the endoplasmic reticulum (ER). Molecular chaperones and folding machinery aid in folding protein into its native structure. This native state is not a random one but is instead the result of both the amino acid sequence and the complex folding network. These properly folded proteins are transported out of the ER for further processing. The path from gene to protein is composed of many different and unknown interactions between DNA, RNA, proteins, and small molecules. Protein folding is one network, or subsystem, within the larger system of protein production. A systems biology approach offers us an opportunity to understand the complicated network of protein folding and the emergent properties that arise from interacting
C.I. Sandefur () Center for Computational Medicine and Bioinformatics, University of Michigan, 2017 Palmer Commons, 100 Washtenaw Ave, Ann Arbor, MI 48105, USA e-mail: [email protected]
W. Dubitzky et al. (eds.), Understanding the Dynamics of Biological Systems: Lessons Learned from Integrative Systems Biology, DOI 10.1007/978-1-4419-7964-3 1, c Springer Science+Business Media, LLC 2011
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C.I. Sandefur and S. Schnell
network components. In this chapter, we explore two models of protein folding and misfolding to investigate how the protein folding network affects protein homeostasis. Using these models, we can identify the protein quality control pathways regulating folding and offer potential therapeutic targets for protein folding diseases.
1.1.1 Disruptions to the Protein Folding Network are Associated with Disease Protein folding is often described by way of a folding energy landscape (Fig. 1.1) (Chiti and Dobson 2006). The landscape is composed of different conformati
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