Allostery in the LacI/GalR family: variations on a theme

Abstract

SummaryThe lactose repressor protein (LacI) was among the very first genetic regulatory proteins discovered, and more than 1000 members of the bacterial LacI/GalR family are now identified. LacI has been the prototype for understanding how transcription is controlled using small metabolites to modulate protein association with specific DNA sites. This understanding has been greatly expanded by the study of other LacI/GalR homologues. A general picture emerges in which the conserved fold provides a scaffold for multiple types of interactions -including oligomerization, small molecule binding, and protein•protein binding -that in turn influence target DNA binding and thereby regulate mRNA production. Although many different functions have evolved from this basic scaffold, each homologue retains functional flexibility: For the same protein, different small molecules can have disparate impact on DNA binding and hence transcriptional outcome. In turn, binding to alternative DNA sequences may impact the degree of allosteric response. Thus, this family exhibits a symphony of variations by which transcriptional control is achieved. Overview of the LacI/GalR familyIn virtually all bacteria, LacI/GalR family members regulate transcription for a wide range of processes. First catalogued in 1992 by Weickert and Adhya [1], sequences of >1000 characterized and hypothetical homologues are now known (2008 BLAST search of SwissProt). These proteins have not been found in archaebacteria or eukaryotes, although proteins with homologous domains are ubiquitous.The LacI/GalR family can be divided into >33 paralogue groups that appear to derive from an ancestral gene. As many as 22 paralogues co-exist in a single species. Many members coordinate available nutrients with expression of catabolic genes [1], but some regulate processes as diverse as nucleotide biosynthesis and toxin expression (e.g. [2,3]). Two members are "master" regulators: homologues CcpA and CRA control expression of enzymes that determine carbon flow in Gram-negative and Gram-positive bacteria, respectively. If these key proteins are disabled, virulence is altered in several pathogens (e.g. [4,5•,6•,7]).The common function of the LacI/GalR proteins, which features allosteric regulation of DNA binding to modulate transcription, is shown in Figure 1. Each homologue has evolved a unique variation: In addition to binding specific "operator" DNA sequences, each protein exhibits specificity for distinct effector ligands. Although most members repress transcription, someCorresponding Author: Swint-Kruse, Liskin (E-mail: lswint-kruse@kumc.edu). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, a...

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