Review
Structure and function of the LysR-type
transcriptional regulator (LTTR)family proteins
Sarah E.Maddocks 1and Petra C.F.Oyston 2
Correspondence Sarah E.Maddocks
sarah.maddocks@bristol.ac.uk
1
licenplateDepartment of Oral and Dental Science,University of Bristol,Lower Maudlin Street,Bristol BS12LY,UK
2
Biomedical Sciences,DSTL Porton Down,Salisbury SP40JQ,UK
The LysR family of transcriptional regulators reprents the most abundant type of transcriptional regul
ator in the prokaryotic kingdom.Members of this family have a conrved structure with an N-terminal DNA-binding helix–turn–helix motif and a C-terminal co-inducer-binding domain.Despite considerable conrvation both structurally and functionally,LysR-type transcriptional regulators (LTTRs)regulate a diver t of genes,including tho involved in virulence,metabolism,quorum nsing and motility.Numerous structural and transcriptional studies of members of the LTTR family are helping to unravel a compelling paradigm that has evolved from the original obrvations and conclusions that were made about this family of transcriptional regulators.
Introduction
The LysR-type transcriptional regulator (LTTR)family is a well-characterized group of transcriptional regulators.They are highly conrved and ubiquitous amongst bacteria,with functional orthologues identified in archaea
and eukaryotic organisms (Pe
´rez-Rueda &Collado-Vides,2001;Sun &Klein,2004;Stec et al.,2006).The LTTR family was formally documented by Henikoff et al.(1988),who concluded that there were at least nine functionally similar transcriptional regulatory proteins (identified in Escherichia coli ,Salmonella enterica rovar Typhim
urium,Rhizobium spp.and Enterobacter cloacae )which on the basis of quence similarity and DNA-binding-domain (DBD)conrvation,could be distinguished as a related group of bacterial transcriptional regulators.Extensive amino acid and dot-matrix comparisons assisted in the
identification of additional,putative LTTRs,expanding the family considerably.LysR,the transcriptional activator of lysA (encoding diaminopimelate decarboxyla,an enzyme that catalys the decarboxylation of diaminopimelate to
produce lysine),had been the subject of considerable study at the molecular level and was the best characterized of the group at this time,hence becoming the family namesake (Stragier et al.,1983;Stragier &Patte,1983).Since then,numerous LTTRs have been identified,and this family of regulators is continually increasing in size.Currently it compris the largest known family of prokaryotic DNA-binding proteins,with 800members identified on the basis of their amino acid quence (Schell,1993).Originally LTTRs were described as transcriptional activa-tors of a single divergently transcribed gene,which exhibited negative autoregulation (Lindquist et al.,1989;Schell,1993;Park et al.,1994a).Extensive rearch has now led to them being regarded as global transcriptional regulators,acting as either activators or repressors of single or operonic genes;they are often divergently transcribed but can be located elwhere on the bacterial chromoso
me
(Heroven &Dersch,2006;Herna
´ndez-Lucas et al.,2008).Co-inducers are recognized as being important for the function of LTTRs and often appear to contribute to a feedback loop in which a product or intermediate of a given metabolic/synthesis pathway (usually activated by an LTTR)acts as the co-inducer necessary for transcriptional activation or repression (Fig.1)(Celis,1999;van Keulen et al.,2003;Picossi et al.,2007).
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The conrvation of LTTRs within the genomes of extremely diver bacteria means that they have evolved a regulatory role over genes with similarly diver
functions,who products can be involved in metabo-lism,cell division,quorum nsing,virulence,motility,nitrogen fixation,oxidative stress respons,toxin production,attachment and cretion,to name a few (Table 1)(Kovacikova &Skorupski,1999;Deghmane et al.,2000,2002;Cao et al.,2001;Kim et al.,2004;Rusll et al.,2004;Byrne et al.,2007;Lu et al.,2007;Sperandio et al.,2007).This review aims to bring
together the increasing body of knowledge concerning the structure,functions and molecular genetics that is
helping to unravel the paradigm of the largest group of transcriptional regulators identified within the pro-karyotic kingdom.
polo shirtAbbreviations:ABS,activation binding site;DBD,DNA-binding domain;HTH,helix–turn–helix;wHTH,winged-HTH;LTTR,LysR-type transcrip-tional regulator;RBS,regulatory binding site.
Microbiology (2008),154,3609–3623DOI 10.1099/mic.0.2008/022772-0
南宁会计培训2008/022772G 2008SGM Printed in Great Britain英语台词
3609
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The origin and evolution of LTTRs
LTTRs are thought to be evolutionarily distinct and to have arin in bacteria;strong evidence suggests that they can be acquired by horizontal transfer(discusd below).The common evolutionary descent of LTTRs is strongly implied from the study of amino acid and DNA quence similarity,which suggests considerable structural and functional homology.Orthologues of LTTRs are
prent in numerous species of bacteria and have retained a conrved structure and function.Multiple paralogues of LTTRs can be prent within a given genome;the are likely to have arin by gene duplication.Subquent evolutionary pressures and genetic divergence have led to the emergence of groups of orthologous paralogues of LTTRs.The remain structurally and functionally similar but have diverged to govern distinct regulons that often exhibit little or no cross-talk.Examples include the Nod and RubisCO subfamilies of LTTRs that are found conrved amongst numerous bacteria and are discusd later in the review.
The helix–turn–helix(HTH)DNA-binding domain Despite the size of the LTTR family and the diver function of LTTR-regulated genes,important structural regions remain highly conrved.LTTRs compri approxi-mately330amino acids;at the C terminus is a co-factor-binding domain and at the N terminus is a helix–turn–helix(HTH)motif,which provides a means of binding to DNA(Fig.2).The HTH motif is prent in all LTTRs and approximately95%of all prokaryotic DNA-binding proteins.This far exceeds the number of other DNA-binding motifs,which include the helix–loop–helix,zinc-finger or b-sheet-anti-parallel domain,which make up the remaining5%(Pe´rez-Rueda&Collado-Vides,2001; Huffman&Brennan,2002;Aravind et al.,2005).The ‘ancestral’HTH motif compris a three-helical bundle with an open conformation.The cond and third helices of the bundle interact with DNA,the t
quintuplets
abjurehird being inrted into the major groove of the DNA double helix(Brennan&Matthews,1989;Huffman&Brennan,2002;Aravind et al., 2005).This so-called universal common ancestor has given ri to a number of variations that still carry out the same regulatory function;the include the winged-helix variety (of which the LysR family is a member)which posss a b-pleated sheet hairpin between the cond and third helix, the ribbon helix–helix structure and the tetra-helical structure(Fig.3).
Most HTH-containing transcriptional regulators fall into two distinct groups,transcriptional activators or repres-sors.Transcriptional activators characteristically have the HTH located at the C terminus,whereas transcriptional repressors have the HTH at the N terminus(Pe´rez-Rueda &Collado-Vides,2000).The LTTRs form a unique group, and have been termed dual regulators,in which the HTH is located20–90amino acids from the N terminus,regardless of whether the LTTR is activating or repressing the transcription of itlf or the gene(s)it is regulating(Fig.4) A comprehensive phylogenetic tree compiled from amino acid quence alignments inferred three putative subgroups of LTTRs(Schlaman et al.,1992b).Whether the subgroups are likely to be‘true’subgroups is uncertain given the reliance upon amino acid quence alone as a basis;the regulators associated with each of the three groups have no particular defining factor,they do not nec
essarily regulate the same target genes(or tho with a similar function)and they do not have the same co-inducer or origin.
Horizontal transfer of LTTRs
LTTRs are found throughout the different subdivisions of proteobacteria,with the majority reprented in the a and c subdivisions.Far fewer LTTRs have been identified for the b subdivision and the Gram-positives,and none have been identified in the d subdivision(Schell,1993).This is unlikely to be a true reprentation of the distribution of LTTRs amongst the different subdivisions and most likely reflects the extent of genetic characterization of members
of S.E.Maddocks and P.C.F.Oyston
3610Microbiology154
the subdivisions.The genes encoding LTTRs have a characteristically high G +C content,due to the distinct Lys/Arg ratio that is common to LTTR proteins (Henikoff et al.,1988;Viale et al.,1991).A number of LTTRs are found on transmissible regions of DNA,and the distinctive G +C percentage has enabled LTTRs that have been acquired by horizontal transfer to be identified within the genomes of many bacteria.
A well-documented example in which an LTTR has been acquired by horizontal transfer relates to the genes encoding ribulo-1,5-bisphosphate carboxyla/oxygena (RubisCO)in the non-sulphur purple photosynthetic bacteria.It has been long established that Rhodobacter spp.have two forms of RubisCO (form I and form II).Comparisons of the form I complex between Rhodobacter capsulatus and R.sphaeroides provided evidence that they were more divergent than previously anticipated (Paoli et al.,1998;Horken &Tabita,1999).Phylogenetic studies confirmed that the form I complex of R.capsulatus was more cloly related to the ‘green-type’RubisCO group,associated with a /b /c chemoautotrophic proteobacteria,and green algae,than the ‘red-type’found in a /b bacteria and the plastids of red algae.The genes encoding the form I
RubisCO complex are operonic (cbbLSQ )and have a divergently transcribed LTTR (CbbR)that activates transcription in respon to light intensity and CO 2concentration (Gibson &Tabita,1993).M
olecular analysis of R.capsulatus indicated that CbbR had been acquired by horizontal transfer with the cbb operon.Form II was also shown to have its own endogenous CbbR divergently transcribed from the cbbM gene.The regulators are currently referred to as CbbR I and CbbR II (Paoli et al.,1998).A classical LTTR box (TTA-N 7/8-TAA)is found upstream of both cbbLSQ and cbbM .R.sphaeroides has only one CbbR,which globally regulates both form I and form II (Smith &Tabita,2002;Dubbs &Tabita,2003;Dubbs et al.,2004).The additional level of regulation conferred on form I of R.capsulatus allows independent regulation of the two operons;the advantage of this,and whether each regulator responds to a different envir-onmental signal,remains to be elucidated.
This is not the only example of the co-acquisition of LTTRs and their associated genes.Numerous LTTR-regulated virulence factors and antibiotic-resistance factors have been identified as having been acquired by horizontal transfer.The include SpvR of Salmonella spp.,which regulates a four-gene operon that is carried on a 90kbp virulence plasmid.The products of the spv operon have a role in bacterial dismination from the Peyer’s patches to the liver and spleen (Caldwell &Gulig,1991;Sheehan &Dorman,1998).Additionally,the acquisition of antibiotic resistance in Pudomonas aeruginosa is reliant upon the expression of a metallo-b -lactama,which is regulated by a divergently transcribed LTTR (Toleman et al.,2002).The LTTRs specifically regulate
the genes they are transferred with and do not tend to be global transcriptional regulators.Structure and function of LTTRs
女性英文名字The role of the C-terminal co-inducer-binding domain Studies of amino acid composition and condary structure have helped to identify many LTTRs;residues 20–80are the most highly conrved and are directly involved with DNA interaction at the major groove.Converly,there is relatively little conrvation at the amino acid level for the C terminus of LTTRs.This region compris two distinct a /b subdomains (RD1and RD2)which are connected by two cross-over regions that form a hinge or cleft,which
is
Fig.2.A schematic reprentation of a typical LTTR (adapted from SMART Pfam domain bl-heidelberg.de)using li LysR protein quence (311amino acids).The N-terminal HTH domain and the LysR-substrate binding region which contains RD1and RD2are indicated.Between RD1and RD2lies the co-inducer-binding cleft.Data suggest that an additi
onal DNA interaction site and co-factor binding residues lie near or within RD1and RD2,
respectively.
Fig.3.Three-dimensional reprentations of common tri-helical HTH DNA-binding motifs (adapted from protein databa struc-tures 1k78and 1smt using Rasmol).(A)is the ‘ancestral’HTH,which is a three-helical bundle in an open conformation;(B)is a winged-HTH and has a single anti-parallel b -sheet region (LysR family members have this variety).LysR family transcriptional regulators
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