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<StructureSection load='1rio' size='340' side='right' caption='Structure of sigma factor region 4 (red) complex with DNA, repression protein CI (grey and green), MPD and Ca+2 (green) (PDB code [[1rio]]).' scene=''>
<StructureSection load='4lup' size='340' side='right' caption='Structure of sigma factor of E.Coli RNAP (grey) in complex with promoter DNA and ethylene glycol (PDB code [[4lup]]).' scene=''>


== Overview ==
== Overview ==


'''Sigma (σ) factor''' is the peoptide subunit needed for the initiation of RNA transcription in prokaryotic organisms <scene name='59/591940/Sigma_factor_in_enzyme/1'>as seen here</scene>.  As opposed to eukaryotes, who utilize a variety of proteins to initiate gene transcription, prokaryotic transcription is initiated almost completely by a σ-factor.  The large and biologically essential protein, RNA polymerase (RNAP), contains one σ-subunit, which binds <scene name='59/591940/Dna_promoter/1'>Promoter Sequences</scene>, located upstream of transcription start sites.  
'''Sigma (σ) factor''' is the peoptide subunit needed for the initiation of RNA transcription in prokaryotic organisms <scene name='59/591940/Sigma_factor_in_enzyme/1'>as seen here</scene>.  As opposed to eukaryotes, who utilize a variety of proteins to initiate gene transcription, prokaryotic transcription is initiated almost completely by a σ-factor.  The large and biologically essential protein, RNA polymerase (RNAP), contains one σ-subunit, which binds <scene name='59/591940/Dna_promoter/3'>DNA promoter sequences</scene>, located upstream of transcription start sites. <br />
*'''Sigma factor 70''' or '''RpoD''' is the primary initiation factor during exponential growth.  <br />
*'''Sigma factor 45''' or '''RpoN''' is responsible for the expression of genes involved in Arg catabolism.<br />
*'''Sigma factor 38''' or '''RpoS''' acts as the master regulator of the general stress response in ''E. coli'' .<br />


== Specific Function and Structure ==
== Function and Structure ==


The '''σ-factor''' performs two chief functions: to direct the catalytic core of RNAP to the +1 start site of transcription, and finally to assist in the initiation of strand seperation of double-helical DNA, ultimately forming the transcription "bubble."  Each gene promoter utilizes a specific promoter region about 40 bp upstream of the transcription start site,  and therefore different σ-factors play a role in the regulation of different genes.  This process, which includes association of the σ-factor with RNAP to recognize and open DNA at the promoter site, followed by dissociation of the σ to allow elongation, is referred to as the '''σ cycle'''.
The '''σ-factor''' performs two chief functions: to direct the catalytic core of RNAP to the  promotoer upstream of the +1 start site of transcription, and finally to assist in the initiation of strand seperation of double-helical DNA, forming the transcription "bubble."[1] Each gene promoter utilizes a specific promoter region about 40 bp upstream of the transcription start site,  and therefore different σ-factors play a role in the regulation of different genes [2].  This process, which includes association of the σ-factor with RNAP to recognize and open DNA at the promoter site, followed by dissociation of the σ to allow elongation, which can then activate additional RNAP enzymes, is referred to as the '''σ-cycle''' [3].


===Domains===
===Domain Strucure & DNA interactions===


There are many types of σ-subunits, and each recognizes a unique promoter sequence.  Furthmore, each σ is composed of a variable number of structured domains.  The simplest σ-factors have two domains, few have three, and others, called '''housekeeping σ-factors''' have 4 domains.  Each of these domains has DNA-binding determinants, or motifs that recognize specific sequences and conformations in DNA.  Most commonly, these recognized motifs occur at the -35 and -10 locations upstream of the +1 site.  One such DNA binding motif, '''the helix-turn-helix motif''' <scene name='59/591940/Hth_motif/1'>HTH</scene>, helps specifically recognize DNA promoters at both the -35 and -10 positions.  This HTH motif, used by most σ-factors, maintains its specificity and accuracy by binding in the '''major groove''' of DNA, where it can interact with the base pairs in the DNA double-helix.  In many prokaryotes, these portions of DNA maintain consensus adenosine and thymine sequences, such as <scene name='59/591940/Ta_sequence/1'>TATAAT</scene>.
There are many types of σ-subunits, and each recognizes a unique promoter sequence.  Furthmore, each unique σ is composed of a variable number of structured domains.  The simplest σ-factors have two domains, few have three, and most, called '''housekeeping σ-factors''', have 4 domains, given the names σ(4), σ(3), σ(2), and σ(1.1) [1,3].  All domains are linked by very flexible peptide '''linkers''' which can extend very long  distances.  Each of these domains utilizes DNA-binding determinants, or domains that recognize specific sequences and conformations in DNA.  Most commonly, these recognized sequences occur at the -35 and -10 locations upstream of the +1 site.  One such DNA-binding motif, '''the helix-turn-helix motif''' (<scene name='59/591940/Hth_motif/2'>HTH</scene>), helps specifically recognize DNA promoters at both the -35 and -10 positions [1].  This HTH motif, used by most σ-factors, maintains its specificity and accuracy by binding in the '''major groove''' of DNA, where it can interact with the base pairs in the DNA double-helix.  In many prokaryotes, these portions of DNA maintain consensus adenosine and thymine sequences [1,2], such as <scene name='59/591940/Ta_sequence/1'>TATAAT</scene>.


===Restriction===
===Transcription Bubble===
Normally, σ-factor domains cannot bind to promoters.  These domains usually are placed in very compacted positions relative to each other, a conformation that buries DNA-binding determinants.  This type of restriction is called '''conformational restriction'''.  Additionally, in housekeeping σs, a domain called the '''σ(1.1)''' stabilizes the compact conformation mentioned above, thereby preventing any promoter recognition.
The <scene name='59/591940/Transcription_bubble/1'>transcription bubble</scene>, also referred to as the '''open complex''' is formed through the common '''housekeeping σ factors''' which unwind about 13 bp of duplex DNA in an ATP independent process.  Research has shown that σ factors require invariant basic and aromatic residues (Phe, Tyr, Trp) critical for this formation [1]. The process of bubble formation begins at the -11 formation (usually A) and propogates to +1 site, through a phenomenon called <scene name='59/591940/Transcription_bubble_flipped/1'>Base Flipping</scene>, which interrupts the stacking interactions stabilizing the double helix conformation [1].  As this process occurs and the DNA transitions into the open promoter complex, certain RNAP-σ contacts are lost, initiating the dissociation of σ.  In summary, the processes of -35 and -10 motif sequence recognition and helix strand separation are coupled by the σ factor.


===Transcription Bubble===
==Restriction==
The <scene name='59/591940/Transcription_bubble/1'>transcription bubble</scene> is fundamentally formed through the common '''housekeeping σ factors''' which unwind about 13 bp of duplex DNA in an ATP independent process.  As such, σ factors require invariant basic and aromatic residues (Phe, Tyr, Trp) critical for this formation.  The process of bubble formation begins at the -11 formation (usually A) and propogates to +1 site, through "base flipping" which interrupts the stacking interactions stabilizing the double helix conformation.  As a result, -35 and -10 motif sequence recognition and strand separation are both coupled by the σ factor.
Initiation of prokaryotic transcription requires cooperation between the σ peptide and RNAP.  Without these fundamental interactions, no transcription is possible.


== Gene Regulation and Differentiation ==
===Comformational and Autoinhibitory===
Normally, σ-factor domains cannot bind to promoters on their own.  These domains usually are placed in very compacted positions relative to each other, a conformation that buries DNA-binding determinants.  This type of restriction is called '''conformational restriction'''[1].  Additionally, in housekeeping σs, a domain called the '''σ(1.1)''' stabilizes the compact conformation mentioned above, thereby preventing any promoter recognition.  This method of restricting the binding abilities of isolated σ's is called '''autoinhibitory inhibition'''[1]. 


===anti-σ's===
An additional method of restriction is through the action of '''anti-σ's''', which act by making stable interactions with σ-domains, such as σ
(4), which allows them to make energy-favorable interactions with RNAP residues. This causes a cascading "peeling off" effect of other σ-domains from the RNAP, preventing any interaction with duplex DNA and inhibiting transcription in an analogous process to competitive inhibition [3].


== Structural highlights ==
== Gene Regulation and Differentiation ==
Since σ-factors are exclusively linked to gene expression in prokaryotic organisms, the variety of σ-factors in a cell dictate how and what genes are transcribed.  Specialized function in cells, therefore, is highly moderated by its arsenal of σ-subunits.  In fact, cellular development and differentiation are directly impacted and carried out by "cascades" of σ-factors. In the early stages of development, '''early genes'''[2] are transcribed by basic '''bacterial σ-factors'''.  These genes are therefore transcribed to give new σ-factors, which in turn activate additional genes, and so on [2].  This process of σ-factor cascades demonstrates the versatile and essential biologic functions of the RNAP subunit, σ.


==3D structures of sigma factor==
==3D structures of sigma factor==
[[Sigma factor 3D structures]]


Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}
</StructureSection>


===Sigma factor===
== References ==


[[1ku2]] – TaSF region 1.2-3.1 – ''Thermus aquaticus''<br />
1. Felklistov, Andrey, Brian D. Sharon, Seth A. Darst, and Carol A. Gross. "Bacterial Sigma Factors: A Historical, Structural, and Genomic Perspective." The Annual Review of Microbiology 68 (2014): 357-76.
[[1ku3]] – TaSF region 4 (mutant)<br />
[[3les]] – TaSF residues 93-271<br />
[[1sig]] – EcSF – ''Escherichia coli''<br />
[[2mao]] – EcSF region 2 - NMR<br />
[[1tty]] – TmSF-70 region 4 – ''Thermotoga maritima''<br />
[[1tty]] – TmSF-70 region 1.1 (mutant) - NMR<br />
[[2ahq]] – AaSF-54 C terminal – ''Aquifex aeolicus'' - NMR<br />
[[2k9l]], [[2k9m]] – AaSF-54 core domain - NMR<br />
[[3mzy]] – SF-H – ''Fusobacterium nucleatum''<br />
 
===Sigma factor complex with DNA===
 
[[3ugo]], [[3ugp]] - TaSF region 2 + DNA<br />
[[4ki2]] - TaSF region 2-3 + DNA<br />
[[2h27]] – EcSF-E region 4 + DNA<br />
[[2map]] – EcSF region 2 + DNA - NMR<br />
[[2o8k]], [[2o9l]] – AaSF-54 C terminal + DNA - NMR<br />
 
===Sigma factor complex with protein===
 
[[3lev]] – TaSF residues 93-271 + antibody<br />
[[1or7]] – EcSF-E + σ-E factor negative regulatory protein <br />
[[4lup]] – EcSF residues 3-92 + EcSF region 2 <br />
[[1tlh]] – EcSF-70 region 4 + anti-σ factor<br />
[[2p7v]] – EcSF-70 region 4 + regulator of σ D<br />
[[1rp3]], [[1sc5]] – AaSF-28 + anti-σ factor FLGM <br />
[[3hug]] – MtSF + membrane protein – ''Mycobacterium tuberculosis''<br />
[[4nqw]] – MtSF-K region 4 + anti-σ factor<br />
[[3wod]] – TtSF + RNAP subunits α,β,β’,ω - ''Thermus thermophilus'' <br />
[[4mq9]] – TtSF-70 + RNAP subunits α,β,β’,ω + antibiotic <br />
[[1l9u]] – TaSF region 1.1-4 + RNAP subunits α,β,β’,ω<br />
[[4mex]] – EcSF-70 + RNAP subunits α,β,β’,ω + antibiotic <br />
[[4mey]], [[4ljz]], [[4lk1]] – EcSF-70 + RNAP subunits α,β,β’,ω <br />
[[4lk0]], [[4llg]] – EcSF-70 + EcRNAP subunits α,β,β’,ω + RNAP inhibitor<br />
[[4cxf]] – SF CNRH + CNRY – ''Cupriavidus metallidurans''<br />
[[4g6d]], [[4g8x]], [[4g94]] – SF-70 region 4 + Orf067 – ''Staphylococcus aureus''<br />
 
===Sigma factor complex with protein and DNA===
 
[[1rio]] - TaSF region 4 + repression protein CI + DNA<br />
[[4oin]], [[4oip]], [[4oiq]], [[4oir]] – TtSF-A + RNAP subunits α,β,β’,ω + antibiotic + DNA<br />
[[4oio]] – TtSF-A + RNAP subunits α,β,β’,ω + DNA<br />
[[3n97]] – TaSF region 4 + RNAP subunits α + DNA<br />
[[1l9u]] – TaSF + RNAP subunits α,β,β’,ω + DNA – Cryo EM  <br />
[[3iyd]] – EcSF-70 + EcRNAP subunits α,β,β’,ω + catabolite gene activator + DNA<br />
 
== References ==


Felklistov, Andrey, Brian D. Sharon, Seth A. Darst, and Carol A. Gross. "Bacterial Sigma Factors: A Historical, Structural, and Genomic Perspective." The Annual Review of Microbiology 68 (2014): 357-76.  
2.  Voet, Donald, Judith G. Voet, and Charlotte W. Pratt. Fundamentals of Biochemistry: Life at the Molecular Level. 3rd ed. Hoboken, NJ: Wiley, 2008.


Voet, Donald, Judith G. Voet, and Charlotte W. Pratt. Fundamentals of Biochemistry: Life at the Molecular Level. 3rd ed. Hoboken, NJ: Wiley, 2008.
3.  Mooney, R. A., S. A. Darst, and R. Landick. "Sigma and RNA Polymerase: An On-again, Off-again Relationship?" Molecular Cell 20.3 (2005): 335-45.


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[[Category:Topic Page]]
[[Category:Topic Page]]
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