The lactose repressor system: paradigms for regulation, allosteric behavior and protein folding

Abstract

In 1961, Jacob and Monod proposed the operon model for gene regulation based on metabolism of lactose in Escherichia coli. This proposal was followed by an explication of allosteric behavior by Monod and colleagues. The operon model rationally depicted how genetic mechanisms can control metabolic events in response to environmental stimuli via coordinated transcription of a set of genes with related function (e.g. metabolism of lactose). The allosteric response found in the lactose repressor and many other proteins has been extended to a variety of cellular signaling pathways in all organisms. These two models have shaped our view of modern molecular biology and captivated the attention of a surprisingly broad range of scientists. More recently, the lactose repressor monomer was used as a model system for experimental and theoretical explorations of protein folding mechanisms. Thus, the lac system continues to advance our molecular understanding of genetic control and the relationship between sequence, structure and function.

DNA supercoiling is a fundamental regulatory principle in the control of bacterial gene expression

“…Although the expression of this information is controlled at multiple levels, regulation at the level of transcription initiation allows a gene to be controlled at the earliest stage of its expression. The literature is replete with examples of regulatory proteins that control transcription initiation and the history of the field is dominated by examples of proteindependent control mechanisms, such as those controlling the life cycle of bacteriophage lambda or the expression of the lac operon (Lewis 2011;Oppenheim et al 2005;Wilson et al 2007). Research that has focused intensively on protein regulators for more than five decades has pushed the regulatory role of DNA into the background where, at best, it is regarded as contributing to gene control by providing cis-acting sites for the binding of regulatory proteins or through its possession of a structural flexibility that facilitates interactions between bound proteins via DNA looping (Schleif 2013;Semsey et al 2005).…”

Structural insights into transcription complexes

“…The expression of genes involved in the lactose metabolism of Escherichia coli is effectively controlled by the Lac repressor (Wilson et al, 2007). The presence of multiple Lac repressor operator binding sites within the lac operon is responsible for the effective down regulation of these genes.…”

From Binary to Multivalued to Continuous Models: The lac Operon as a Case Study

“…The lac operon in E. coli consists of three different structural genes that are transcribed as a single mRNA [11] in response to a certain glucose/lactose ratio. This polycistronic lacZYA mRNA is translated into three proteins, which are required to import and digest the disaccharide lactose.…”

“…As a case study we chose the well-described lac operon, the paradigmatic example for a gene regulatory system in prokaryotes [10][11][12]. The involvement of species from metabolic, signaling and gene regulatory network layers and also the existence of feedback loops in the regulation of the lac operon make it a very attractive system to evaluate different modeling approaches.…”