View source for Sigma factor

{{Short description|Protein needed for initiation of transcription in prokaryotes}}
A '''sigma factor''' ('''σ factor''' or '''specificity factor''') is a protein needed for initiation of [[Transcription (biology)|transcription]] in [[bacteria]].<ref name="gross">{{cite journal | vauthors = Gruber TM, Gross CA | title = Multiple sigma subunits and the partitioning of bacterial transcription space | journal = Annual Review of Microbiology | volume = 57 | pages = 441–66 | year = 2003 | pmid = 14527287 | doi = 10.1146/annurev.micro.57.030502.090913 }}</ref><ref name="Kang">{{cite journal | vauthors = Kang JG, Hahn MY, Ishihama A, Roe JH | title = Identification of sigma factors for growth phase-related promoter selectivity of RNA polymerases from Streptomyces coelicolor A3(2) | journal = Nucleic Acids Research | volume = 25 | issue = 13 | pages = 2566–73 | date = July 1997 | pmid = 9185565 | pmc = 146787 | doi = 10.1093/nar/25.13.2566 }}</ref> It is a [[bacterial transcription]] initiation factor that enables specific binding of [[RNA polymerase]] (RNAP) to gene [[promoter (biology)|promoter]]s. It is homologous to [[archaeal transcription factor B]] and to [[Eukaryote|eukaryotic]] factor [[TFIIB]].<ref>{{cite journal | vauthors = Burton SP, Burton ZF | title = The σ enigma: bacterial σ factors, archaeal TFB and eukaryotic TFIIB are homologs | journal = Transcription | volume = 5 | issue = 4 | pages = e967599 | date = 6 November 2014 | pmid = 25483602 | pmc = 4581349 | doi = 10.4161/21541264.2014.967599 }}</ref> The specific sigma factor used to initiate transcription of a given gene will vary, depending on the [[gene]] and on the environmental signals needed to initiate transcription of that gene. Selection of promoters by RNA polymerase is dependent on the sigma factor that associates with it.<ref>{{cite journal | vauthors = Ho TD, Ellermeier CD | title = Extra cytoplasmic function σ factor activation | journal = Current Opinion in Microbiology | volume = 15 | issue = 2 | pages = 182–8 | date = April 2012 | pmid = 22381678 | pmc = 3320685 | doi = 10.1016/j.mib.2012.01.001 }}</ref> They are also found in plant [[chloroplast]]s as a part of the bacteria-like plastid-encoded polymerase (PEP).<ref name=pmid20701995>{{cite journal | vauthors = Schweer J, Türkeri H, Kolpack A, Link G | title = Role and regulation of plastid sigma factors and their functional interactors during chloroplast transcription - recent lessons from Arabidopsis thaliana | journal = European Journal of Cell Biology | volume = 89 | issue = 12 | pages = 940–6 | date = December 2010 | pmid = 20701995 | doi = 10.1016/j.ejcb.2010.06.016 }}</ref>

The sigma factor, together with RNA polymerase, is known as the RNA polymerase [[Enzyme#Cofactors|holoenzyme]]. Every molecule of RNA polymerase holoenzyme contains exactly one sigma factor subunit, which in the model bacterium ''[[Escherichia coli]]'' is one of those listed below.  The number of sigma factors varies between bacterial species.<ref name="gross"/><ref>{{cite journal | vauthors = Sharma UK, Chatterji D | title = Transcriptional switching in Escherichia coli during stress and starvation by modulation of sigma activity | journal = FEMS Microbiology Reviews | volume = 34 | issue = 5 | pages = 646–57 | date = September 2010 | pmid = 20491934 | doi = 10.1111/j.1574-6976.2010.00223.x | doi-access = free }}</ref> ''E. coli'' has seven sigma factors.  Sigma factors are distinguished by their characteristic [[Molecular mass|molecular weights]]. For example, σ<sup>70</sup> is the sigma factor with a molecular weight of 70 [[Dalton (unit)|kDa]].

The sigma factor in the RNA polymerase holoenzyme complex is required for the initiation of transcription, although once that stage is finished, it is dissociated from the complex and the RNAP continues elongation on its own.

==Specialized sigma factors==
Different sigma factors are utilized under different environmental conditions.  These specialized sigma factors bind the promoters of genes appropriate to the environmental conditions, increasing the transcription of those genes.

Sigma factors in ''[[Escherichia coli|E. coli]]'':
*[[RpoD|σ<sup>70</sup>(RpoD)]] – σ<sup>A</sup> – the '''"housekeeping" sigma factor''' or also called as '''primary sigma factor''' (Group 1), transcribes most genes in growing cells.  Every cell has a "housekeeping" sigma factor that keeps essential genes and pathways operating.<ref name="gross"/> In the case of ''E. coli'' and other gram-negative rod-shaped bacteria, the "housekeeping" sigma factor is σ<sup>70</sup>.<ref name="gross"/>  Genes recognized by σ<sup>70</sup> all contain similar promoter [[consensus sequence]]s consisting of two parts.<ref name="gross"/>  Relative to the DNA base corresponding to the start of the RNA transcript, the consensus promoter sequences are characteristically centered at 10 and 35 nucleotides before the start of transcription (−10 and −35).
*[[FecI|σ<sup>19</sup> (FecI)]] – the ferric citrate sigma factor, regulates the ''fec'' gene for iron transport and metabolism
*[[RpoE|σ<sup>24</sup> (RpoE)]] – extreme heat stress response and the extracellular proteins sigma factor
*[[RpoF|σ<sup>28</sup> (RpoF/FliA)]] – the [[Flagellum|flagellar]] synthesis and [[chemotaxis]] sigma factor
*σ<sup>32</sup> (RpoH) – the [[Heat shock response|heat shock]] sigma factor, it is turned on when the bacteria are exposed to heat. Due to the higher expression, the factor will bind with a high probability to the polymerase-core-enzyme. Doing so, other heatshock proteins are expressed, which enable the cell to survive higher temperatures. Some of the enzymes that are expressed upon activation of σ<sup>32</sup> are [[Chaperone (protein)|chaperones]], [[proteases]] and DNA-repair enzymes.
*[[RpoS|σ<sup>38</sup> (RpoS)]] – the starvation/stationary phase sigma factor
*[[RpoN|σ<sup>54</sup> (RpoN)]] – the nitrogen-limitation sigma factor

There are also [[anti-sigma factors]] that inhibit the function of sigma factors and anti-anti-sigma factors that restore sigma factor function.

== Structure ==
[[File:Sigma 70 domains.png|thumb|right|Domain organization, promoter recognition and structural organization of the σ<sup>70</sup> family. ('''a''') The domain organization of σ factors from Groups 1, 3 and 4 are illustrated above σ<sup>70</sup> consensus E. coli promoter DNA. ('''b''') Organization of E. coli σ70 in an RNA polymerase transcription initiation complex. (PDB 4YLN).]]

By sequence similarity, most sigma factors are σ<sup>70</sup>-like ({{InterPro|IPR000943}}). They have four main regions (domains) that are generally conserved:

 N-terminus --------------------- C-terminus
              1.1    2    3    4

The regions are further subdivided. For example, region 2 includes 1.2 and 2.1 through 2.4.

Domain 1.1 is found only in "primary sigma factors" (RpoD, RpoS in ''E.coli''; "Group 1").  It is involved in ensuring the sigma factor will only bind the promoter when it is complexed with the RNA polymerase.<ref name="pmid26131973">{{cite journal | vauthors = Paget MS | title = Bacterial Sigma Factors and Anti-Sigma Factors: Structure, Function and Distribution | journal = Biomolecules | volume = 5 | issue = 3 | pages = 1245–65 | date = June 2015 | pmid = 26131973 | pmc = 4598750 | doi = 10.3390/biom5031245 | doi-access = free }}</ref> Domains 2-4 each interact with specific promoter elements and with RNAP. Region 2.4 recognizes and binds to the promoter −10 element (called the "[[Pribnow box]]"). Region 4.2 recognizes and binds to the promoter −35 element.<ref name="pmid26131973"/>

Not every sigma factor of the σ<sup>70</sup> family contains all the domains. Group 2, which includes RpoS, is very similar to Group 1 but lacks domain 1. Group 3 also lacks domain 1, and includes σ<sup>28</sup>. Group 4, also known as the Extracytoplasmic Function (ECF) group, lack both σ1.1 and σ3. RpoE is a member.<ref name="pmid26131973"/>

{{further|RpoN}}
Other known sigma factors are of the σ<sup>54</sup>/RpoN ({{InterPro|IPR000394}}) type. They are functional sigma factors, but they have significantly different primary amino acid sequences.<ref>{{cite journal | vauthors = Merrick MJ | title = In a class of its own--the RNA polymerase sigma factor sigma 54 (sigma N) | journal = Molecular Microbiology | volume = 10 | issue = 5 | pages = 903–9 | date = December 1993 | pmid = 7934866 | doi = 10.1111/j.1365-2958.1993.tb00961.x | s2cid = 84789281 }}</ref>

<div style="max-width: 100%; overflow-x: scroll; clear: both">
{|class="wikitable mw-collapsible"
|+Protein domain infoboxes
|-
|{{Infobox protein family
| Symbol = Sigma70_r1_1
| Name = Sigma70 region 1.1
| image = 
| width = 
| caption = Autoregulation of a group 1 bacterial sigma factor involves the formation of a region 1.1- induced compacted structure
| Pfam = PF03979
| Pfam_clan =  
| InterPro = IPR007127
| SMART = 
| PROSITE = 
| MEROPS = 
| SCOP = 
| TCDB = 
| OPM family = 
| OPM protein = 
| CAZy = 
| CDD = 
}}
|{{Infobox protein family
| Symbol = Sigma70_r1_2
| Name = Sigma70 region 1.2
| image = PDB 1ku2 EBI.jpg
| width = 
| caption = Crystal structure of ''Thermus aquaticus'' RNA polymerase sigma subunit fragment containing regions 1.2 to 3.1
| Pfam = PF00140
| Pfam_clan =  
| InterPro = IPR009042
| SMART = 
| PROSITE = PDOC00592
| MEROPS = 
| SCOP = 1sig
| TCDB = 
| OPM family = 
| OPM protein = 
| CAZy = 
| CDD = 
}}
|{{Infobox protein family
| Symbol = Sigma70_r2
| Name = Sigma70 region 2
| image = PDB 1sig EBI.jpg
| width = 
| caption = Crystal structure of a sigma70 subunit fragment from ''Escherichia coli'' RNA polymerase
| Pfam = PF04542
| Pfam_clan = CL0123
| InterPro = IPR007627
| SMART = 
| PROSITE = PDOC00592
| MEROPS = 
| SCOP = 1sig
| TCDB = 
| OPM family = 
| OPM protein = 
| CAZy = 
| CDD = 
}}
|{{Infobox protein family
| Symbol = Sigma70_r3
| Name = Sigma70 region 3
| image = PDB 1rp3 EBI.jpg
| width = 
| caption = Solution structure of sigma70 region 3 from ''Thermotoga maritima''
| Pfam = PF04539
| Pfam_clan = CL0123
| InterPro = IPR007624
| SMART = 
| PROSITE = 
| MEROPS = 
| SCOP = 1ku2
| TCDB = 
| OPM family = 
| OPM protein = 
| CAZy = 
| CDD = 
}}
|{{Infobox protein family
| Symbol = Sigma70_r4
| Name = Sigma70 region 4
| image = PDB 1tty EBI.jpg
| width = 
| caption = Solution structure of sigma70 region 4 from ''Thermotoga maritima''
| Pfam = PF04545
| Pfam_clan = CL0123
| InterPro = IPR007630
| SMART = 
| PROSITE = 
| MEROPS = 
| SCOP = 1or7
| TCDB = 
| OPM family = 
| OPM protein = 
| CAZy = 
| CDD = 
}}
|{{Infobox protein family
| Symbol = Sigma70_r4_2
| Name = Sigma70 region 4.2
| image = PDB 2h27 EBI.jpg
| width = 
| caption = Crystal structure of ''Escherichia coli'' sigma70 region 4 bound to its -35 element DNA
| Pfam = PF08281
| Pfam_clan = CL0123
| InterPro = IPR013249
| SMART = 
| PROSITE = 
| MEROPS = 
| SCOP = 1or7
| TCDB = 
| OPM family = 
| OPM protein = 
| CAZy = 
| CDD = 
}}
|}
</div>

==Retention during transcription elongation==
The core RNA polymerase (consisting of 2 alpha (α), 1 beta (β), 1 beta-prime (β'), and 1 omega (ω) subunits) binds a sigma factor to form a complex called the [[RNA polymerase]] [[holoenzyme]]. It was previously believed that the RNA polymerase holoenzyme initiates transcription, while the core RNA polymerase alone synthesizes RNA. Thus, the accepted view was that sigma factor must dissociate upon transition from transcription initiation to transcription elongation (this transition is called "promoter escape"). This view was based on analysis of purified complexes of RNA polymerase stalled at initiation and at elongation. Finally, structural models of RNA polymerase complexes predicted that, as the growing RNA product becomes longer than ~15 nucleotides, sigma must be "pushed out" of the holoenzyme, since there is a steric clash between RNA and a sigma domain. However, σ<sup>70</sup> can remain attached in complex with the core RNA polymerase in early elongation<ref name=Kapanidis>{{cite journal | vauthors = Kapanidis AN, Margeat E, Laurence TA, Doose S, Ho SO, Mukhopadhyay J, Kortkhonjia E, Mekler V, Ebright RH, Weiss S | title = Retention of transcription initiation factor sigma70 in transcription elongation: single-molecule analysis | journal = Molecular Cell | volume = 20 | issue = 3 | pages = 347–56 | date = November 2005 | pmid = 16285917 | doi = 10.1016/j.molcel.2005.10.012 | doi-access = free }}</ref> and sometimes throughout elongation.<ref>{{cite journal |vauthors=Harden TT, Wells CD, Friedman LJ, Landick R, Hochschild A, Kondev J, Gelles J |title=Bacterial RNA polymerase can retain σ70 throughout transcription |journal=Proc Natl Acad Sci U S A |volume=113 |issue=3 |pages=602–7 |date=January 2016 |pmid=26733675 |pmc=4725480 |doi=10.1073/pnas.1513899113 |bibcode=2016PNAS..113..602H |doi-access=free }}</ref> Indeed, the phenomenon of promoter-proximal pausing indicates that sigma plays roles during early elongation. All studies are consistent with the assumption that promoter escape reduces the lifetime of the sigma-core interaction from very long at initiation (too long to be measured in a typical biochemical experiment) to a shorter, measurable lifetime upon transition to elongation.

==Sigma cycle==
It had long been thought that the sigma factor obligatorily leaves the core enzyme once it has initiated transcription, allowing it to link to another core enzyme and initiate transcription at another site. Thus, the sigma factor would cycle from one core to another.
However, [[fluorescence resonance energy transfer]] was used to show that the sigma factor does not obligatorily leave the core.<ref name=Kapanidis /> Instead, it changes its ''binding'' with the core during initiation and elongation. Therefore, the sigma factor cycles between a strongly bound state during initiation and a weakly bound state during elongation.

== Sigma factor competition ==

The number of RNAPs in bacterial cells (e.g., ''E. coli'') have been shown to be smaller than the number of sigma factors. Consequently, if a certain sigma factor is overexpressed, not only will it increase the expression levels of genes whose promoters have preference for that sigma factor, but it will also reduce the probability that genes with promoters with preference for other sigma factors will be expressed.<ref>{{Cite journal |last1=Jishage |first1=M |last2=Ishihama |first2=A |date=December 1995 |title=Regulation of RNA polymerase sigma subunit synthesis in Escherichia coli: intracellular levels of sigma 70 and sigma 38 |journal=Journal of Bacteriology |language=en |volume=177 |issue=23 |pages=6832–6835 |doi=10.1128/jb.177.23.6832-6835.1995 |issn=0021-9193 |pmc=177550 |pmid=7592475}}</ref><ref>{{Cite journal |last1=Jishage |first1=M |last2=Iwata |first2=A |last3=Ueda |first3=S |last4=Ishihama |first4=A |date=September 1996 |title=Regulation of RNA polymerase sigma subunit synthesis in Escherichia coli: intracellular levels of four species of sigma subunit under various growth conditions |journal=Journal of Bacteriology |language=en |volume=178 |issue=18 |pages=5447–5451 |doi=10.1128/jb.178.18.5447-5451.1996 |issn=0021-9193 |pmc=178365 |pmid=8808934}}</ref><ref>{{Cite journal |last1=Grigorova |first1=Irina L. |last2=Phleger |first2=Naum J. |last3=Mutalik |first3=Vivek K. |last4=Gross |first4=Carol A. |date=2006-04-04 |title=Insights into transcriptional regulation and σ competition from an equilibrium model of RNA polymerase binding to DNA |journal=Proceedings of the National Academy of Sciences |language=en |volume=103 |issue=14 |pages=5332–5337 |doi=10.1073/pnas.0600828103 |pmid=16567622 |pmc=1459355 |bibcode=2006PNAS..103.5332G |issn=0027-8424|doi-access=free }}</ref><ref name=":0">{{Cite journal |last1=Kandavalli |first1=Vinodh K. |last2=Tran |first2=Huy |last3=Ribeiro |first3=Andre S. |date=October 2016 |title=Effects of σ factor competition are promoter initiation kinetics dependent |url=https://linkinghub.elsevier.com/retrieve/pii/S1874939916301614 |journal=Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms |language=en |volume=1859 |issue=10 |pages=1281–1288 |doi=10.1016/j.bbagrm.2016.07.011|pmid=27452766 |url-access=subscription }}</ref>

Meanwhile, transcription initiation has two major rate limiting steps: the closed and the open complex formation. However, only the dynamics of the first step depends on the concentration of sigma factors. Interestingly, the faster the closed complex formation relative to the open complex formation, the less responsive is a promoter to changes in sigma factors’ concentration (see <ref name=":0" /> for a model and empirical data of this phenomenon).

== Genes with dual sigma factor preference ==

While most genes of ''E. coli'' can be recognized by an RNAP with one and only one type of sigma factor (e.g. sigma 70), a few genes (~ 5%) have what is called a “dual sigma factor preference”,<ref name=":1">{{Cite journal |last1=Baptista |first1=Ines S.C. |last2=Kandavalli |first2=Vinodh |last3=Chauhan |first3=Vatsala |last4=Bahrudeen |first4=Mohamed N.M. |last5=Almeida |first5=Bilena L.B. |last6=Palma |first6=Cristina S.D. |last7=Dash |first7=Suchintak |last8=Ribeiro |first8=Andre S. |date=April 2022 |title=Sequence-dependent model of genes with dual σ factor preference |journal=Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms |language=en |volume=1865 |issue=3 |pages=194812 |doi=10.1016/j.bbagrm.2022.194812|pmid=35338024 |s2cid=247636833 |doi-access=free |hdl=10362/143501 |hdl-access=free }}</ref> that is, they can respond to two different sigma factors, as reported in RegulonDB.<ref>{{Cite journal |last1=Santos-Zavaleta |first1=Alberto |last2=Salgado |first2=Heladia |last3=Gama-Castro |first3=Socorro |last4=Sánchez-Pérez |first4=Mishael |last5=Gómez-Romero |first5=Laura |last6=Ledezma-Tejeida |first6=Daniela |last7=García-Sotelo |first7=Jair Santiago |last8=Alquicira-Hernández |first8=Kevin |last9=Muñiz-Rascado |first9=Luis José |last10=Peña-Loredo |first10=Pablo |last11=Ishida-Gutiérrez |first11=Cecilia |date=2019-01-08 |title=RegulonDB v 10.5: tackling challenges to unify classic and high throughput knowledge of gene regulation in E. coli K-12 |url=https://academic.oup.com/nar/article/47/D1/D212/5160972 |journal=Nucleic Acids Research |language=en |volume=47 |issue=D1 |pages=D212–D220 |doi=10.1093/nar/gky1077 |issn=0305-1048 |pmc=6324031 |pmid=30395280}}</ref> The most common ones are those promoters that can respond to both sigma 70 and to sigma 38 (iIlustrated in the figure) . Studies of the dynamics of these genes showed that when the cells enter stationary growth they are almost as induced as those genes that have preference for σ38 alone. This induction level was shown to be predictable from their promoter sequence.<ref name=":1" /> A model of their dynamics is shown in the figure. In the future, these promoters may become useful tools in synthetic genetic constructs in ''E. coli''.
[[File:SigmFactModelWikipedia01A.jpg|thumb|'''Left''': illustration of genes whose promoters can be recognized by both sigma 70 (green) and sigma 38 (blue). Shown are the RNA polymerases, carrying the two different sigma factors, and either of them can bind to the promoter region (grey rectangle). '''Right''': Model proposed in [15] of these genes. The model consists of a two-step process of gene expression (transcription followed by translation). The rate constant from transcription (k<sub>t</sub>) accounts for the possibility of binding by either RNAP (those carrying sigma 70, and those carrying sigma 38). The model also includes translation (rate constant kt), and RNA and protein degradation to “nothing” represented by the “slashed zero glyph”. |401x401px|center]]

== See also ==
*[[Ekkehard Bautz]]

== References ==
{{Reflist}}

== External links ==
*{{MeshName|Sigma+Factor}}

{{Transcription factors|g0}}

[[Category:Gene expression]]