Transcription factor II B

Last updated
GTF2B
Protein GTF2B PDB 1c9b.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases GTF2B , TF2B, TFIIB, general transcription factor IIB
External IDs OMIM: 189963; MGI: 2385191; HomoloGene: 1158; GeneCards: GTF2B; OMA:GTF2B - orthologs
Orthologs
SpeciesHumanMouse
Entrez

2959

229906

Ensembl

ENSG00000137947

ENSMUSG00000028271

UniProt

Q00403

P62915

RefSeq (mRNA)

NM_001514

NM_145546

RefSeq (protein)

NP_001505

NP_663521

Location (UCSC) Chr 1: 88.85 – 88.89 Mb Chr 3: 142.47 – 142.49 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Transcription factor II B (TFIIB) is a general transcription factor that is involved in the formation of the RNA polymerase II preinitiation complex (PIC) [5] and aids in stimulating transcription initiation. TFIIB is localised to the nucleus and provides a platform for PIC formation by binding and stabilising the DNA-TBP (TATA-binding protein) complex and by recruiting RNA polymerase II and other transcription factors. It is encoded by the TFIIB gene, [6] [7] and is homologous to archaeal transcription factor B and analogous to bacterial sigma factors. [8]

Structure

TFIIB is a single 33kDa polypeptide consisting of 316 amino acids. [9] TFIIB is made up of four functional regions: the C-terminal core domain; the B linker; the B reader and the amino terminal zinc ribbon.

TFIIB makes protein-protein interactions with the TATA-binding protein (TBP) subunit of transcription factor IID, [10] [11] and the RPB1 subunit of RNA polymerase II. [11]

TFIIB makes sequence-specific protein-DNA interactions with the B recognition element (BRE), a promoter element flanking the TATA element. [12] [13]

Mechanism of action

There are six steps in the mechanism of TFIIB action in the formation of the PIC and transcription initiation: [14]

  1. RNA polymerase II is recruited to DNA through the TFIIB B core and B ribbon.
  2. RNA polymerase II unwinds DNA, aided by the TFIIB B linker and B reader (open complex formation).
  3. RNA polymerase II selects a transcription start site, aided by the TFIIB B reader.
  4. RNA polymerase II forms the first phosphodiester bond.
  5. RNA polymerase II produces short abortive transcripts due to clashes between nascent RNA and the TFIIB B reader loop.
  6. Extension of nascent RNA to 12-13 nucleotides leads to ejection of TFIIB due to further clashes with TFIIB.

Interactions with RNA polymerase II

Each of the functional regions of TFIIB interacts with different parts of RNA polymerase II. The amino terminal B ribbon is located on dock domain of RNA polymerase II and extends in to the cleft towards the active site. Extending the B ribbon is the B reader that extends via the RNA exit tunnel to the binding site of the DNA-RNA hybrid and towards the active site. The B linker is the region between the B reader and the B core that is found in the cleft of RNA polymerase II and continues by the rudder and the clamp coiled-coil until it reaches the C terminal B core that is found above the wall of RNA polymerase II. [14] [15] The B reader and the B linker consist of highly conserved residues that are positioned through the RNA polymerase II tunnel towards the active site and ensure tight binding, without these key residues dissociation would occur. These two domains are also thought to adjust the position of some of the more flexible areas of RNA polymerase II to allow for the precise positioning of the DNA and allowing the addition of the new NTPs onto the nascent RNA chain. [16] Upon binding RNA polymerase II, the B reader and B linker cause slight repositioning of the protrusion domain of RNA polymerase II which allows an essential second magnesium ion to bind in the active site. [17] It forms a beta sheet and an ordered loop that helps with the stability of the structure when transcription is initiated. [15]

Open and closed complexes

The open and closed conformations refer to the state of the DNA and whether the template strand has been separated from the non-template strand within the PIC. The place at which the DNA opens to form the bubble lies above a tunnel that is lined by the B-core, B-linker and B-reader as well as parts of RNA polymerase II. The B linker is found directly aligned with the point at which the DNA opens [18] and in the open complex it is found between the two DNA strands, suggesting that it has a role in promoter melting, but it does not have a role in the catalytic RNA synthesis. Although TFIIB keeps a similar structure in both conformations some of the intramolecular interactions between the core and the B reader are disrupted upon DNA opening.

After DNA melting the transcription initiator (Inr) must be located on the DNA so the TSS can be identified by the RNA polymerase II and transcription can begin. This is done by passing the DNA through the 'template tunnel' and the DNA is scanned, looking for the Inr and placing it in a position that ensures the transcription start site is located in the correct place by the RNA polymerase active site. The B reader of TFIIB is found in the template tunnel and is important in locating the Inr, mutations in the B reader cause the TSS to change and therefore incorrect transcription to occur [19] (although PIC formation and DNA melting still take place). Yeast are a particularly good example of this alignment as the yeast Inr motif has a strictly conserved A residue at position 28 and in the open complex model a complementary T residue can be found in the B reader helix. When this T residue is mutated, transcription was significantly less effective emphasizing the role of the B reader. [14]

The B reader loop is further thought to stabilise NTPs in the active site and, due to its flexibility, allow the nucleic acids to remain in contact during the early synthesis of the RNA molecule (i.e. stabilises the growing RNA-DNA hybrid)

Release

When the RNA transcript reaches 7 nucleotides long, transcription enters the elongation phase, the beginning of which is characterised by the collapsing of the DNA bubble and the ejection of TFIIB. [14] This is thought to be because the nascent RNA clashes with the B linker helix when it is 6 bases long and upon further elongation to 12-13 bases it will clash with the B-reader and B-ribbon leading to dissociation. [17] The DNA duplex also clashes with the B linker above the rudder (caused by rewinding of the DNA into a double helix).

Phosphorylation

TFIIB is phosphorylated at serine 65 which is found in the B reader domain. Without this phosphorylation, transcription initiation does not occur. It has been suggested that the general transcription factor TFIIH could act as the kinase for this phosphorylation although more evidence is needed to support this. Although TFIIB does not travel with the RNA polymerase II complex along the DNA during elongation, it has been recently suggested that it has a role in gene looping which links the promoter to the terminator of the gene. [20] however, recent research has shown that a depletion in TFIIB is not lethal to cells and transcription levels are not significantly affected. [21] This is because over 90% of mammalian promoters do not contain a BRE (B recognition element) or TATA box sequence which are required for TFIIB to bind. In addition to this, TFIIB levels have been shown to fluctuate in different types of cell, and at different points in the cell cycle, supporting the evidence that it is not required for all RNA polymerase II transcription. Gene looping is reliant on the interaction between phosphorylated serine residues found on the C terminal domain of RNA polymerase II and polyadenylation factors. TFIIB is needed for the interaction of promoters with these polyadenylation factors, such as SSu72 and CstF-64. It has also been suggested that both gene loop formation and the collapse of the DNA bubble are a result of TFIIB phosphorylation; however, it is unclear whether this gene loop formation is a cause or consequence of transcription initiation.

Similarities in other transcription complexes

RNA polymerase III uses a very similar factor to TFIIB called Brf (TFIIB-related factor) which also contains a conserved zinc ribbon and C terminal core. However, the structure diverges in the more flexible linker region although Brf still contains highly conserved sequences in the same positions that the B reader and B linker are found. These conserved regions probably carry out similar functions as the domains in TFIIB. RNA polymerase I does not use a factor that is similar to TFIIB; however, it is thought that another unknown factor fulfils the same function. [22] There is no direct homologue for TFIIB in bacterial systems but there are proteins that bind the bacterial polymerase in a similar manner with no sequence similarity. In particular the bacterial protein σ70 [14] contains domains that bind the polymerase at the same points as the B-linker, B-ribbon and B-core. This is especially apparent in the σ 3 region and the region 4 linker which might stabilise the DNA in the polymerase active site. [23]

Clinical significance

Antiviral activity

Recent studies have shown that decreased TFIIB levels do not affect transcription levels within cells, this is thought to be partially because over 90% of mammalian promoters do not contain a BRE or TATA box. However, it has been shown that TFIIB is vital to the in vitro transcription and regulation of the herpes simplex virus. This is thought to be due to similarity TFIIB has to cyclin A. In order to undergo replication, viruses often stop host cells progression through the cell cycle, using cyclins and other proteins. As TFIIB has a similar structure to cyclin A it has been suggested that depleted levels of TFIIB could have antiviral effects. [21]

Neurodegeneration

Studies have shown that the binding of TFIIB to TBP is affected by the length of the polyglutamine tract in TBP. Extended polyglutamine tracts such as those found in neurodegenerative diseases cause increased interaction with TFIIB. [24] This is thought to affect transcription in these diseases as it reduces the availability of TFIIB to other promoters in the brain as the TFIIB is instead interacting with the expanded polyglutamine tracts.

Related Research Articles

<span class="mw-page-title-main">Transcription (biology)</span> Process of copying a segment of DNA into RNA

Transcription is the process of copying a segment of DNA into RNA. The segments of DNA transcribed into RNA molecules that can encode proteins produce messenger RNA (mRNA). Other segments of DNA are transcribed into RNA molecules called non-coding RNAs (ncRNAs).

In molecular biology, the TATA box is a sequence of DNA found in the core promoter region of genes in archaea and eukaryotes. The bacterial homolog of the TATA box is called the Pribnow box which has a shorter consensus sequence.

<span class="mw-page-title-main">Transcription preinitiation complex</span> Complex of proteins necessary for gene transcription in eukaryotes and archaea

The preinitiation complex is a complex of approximately 100 proteins that is necessary for the transcription of protein-coding genes in eukaryotes and archaea. The preinitiation complex positions RNA polymerase II at gene transcription start sites, denatures the DNA, and positions the DNA in the RNA polymerase II active site for transcription.

<span class="mw-page-title-main">General transcription factor</span> Class of protein transcription factors

General transcription factors (GTFs), also known as basal transcriptional factors, are a class of protein transcription factors that bind to specific sites (promoter) on DNA to activate transcription of genetic information from DNA to messenger RNA. GTFs, RNA polymerase, and the mediator constitute the basic transcriptional apparatus that first bind to the promoter, then start transcription. GTFs are also intimately involved in the process of gene regulation, and most are required for life.

<span class="mw-page-title-main">TATA-binding protein</span> Protein-coding gene in the species Homo sapiens

The TATA-binding protein (TBP) is a general transcription factor that binds to a DNA sequence called the TATA box. This DNA sequence is found about 30 base pairs upstream of the transcription start site in some eukaryotic gene promoters.

Transcription factor II D (TFIID) is one of several general transcription factors that make up the RNA polymerase II preinitiation complex. RNA polymerase II holoenzyme is a form of eukaryotic RNA polymerase II that is recruited to the promoters of protein-coding genes in living cells. It consists of RNA polymerase II, a subset of general transcription factors, and regulatory proteins known as SRB proteins. Before the start of transcription, the transcription Factor II D (TFIID) complex binds to the core promoter DNA of the gene through specific recognition of promoter sequence motifs, including the TATA box, Initiator, Downstream Promoter, Motif Ten, or Downstream Regulatory elements.

<span class="mw-page-title-main">Eukaryotic transcription</span> Transcription is heterocatalytic function of DNA

Eukaryotic transcription is the elaborate process that eukaryotic cells use to copy genetic information stored in DNA into units of transportable complementary RNA replica. Gene transcription occurs in both eukaryotic and prokaryotic cells. Unlike prokaryotic RNA polymerase that initiates the transcription of all different types of RNA, RNA polymerase in eukaryotes comes in three variations, each translating a different type of gene. A eukaryotic cell has a nucleus that separates the processes of transcription and translation. Eukaryotic transcription occurs within the nucleus where DNA is packaged into nucleosomes and higher order chromatin structures. The complexity of the eukaryotic genome necessitates a great variety and complexity of gene expression control.

Transcription factor TFIIA is a nuclear protein involved in the RNA polymerase II-dependent transcription of DNA. TFIIA is one of several general (basal) transcription factors (GTFs) that are required for all transcription events that use RNA polymerase II. Other GTFs include TFIID, a complex composed of the TATA binding protein TBP and TBP-associated factors (TAFs), as well as the factors TFIIB, TFIIE, TFIIF, and TFIIH. Together, these factors are responsible for promoter recognition and the formation of a transcription preinitiation complex (PIC) capable of initiating RNA synthesis from a DNA template.

<span class="mw-page-title-main">TAF6</span> Protein-coding gene in the species Homo sapiens

Transcription initiation factor TFIID subunit 6 is a protein that in humans is encoded by the TAF6 gene.

<span class="mw-page-title-main">TAF1</span> Protein-coding gene in the species Homo sapiens

Transcription initiation factor TFIID subunit 1, also known as transcription initiation factor TFIID 250 kDa subunit (TAFII-250) or TBP-associated factor 250 kDa (p250), is a protein that in humans is encoded by the TAF1 gene.

<span class="mw-page-title-main">TAF9</span> Protein-coding gene in the species Homo sapiens

TAF9 RNA polymerase II, TATA box binding protein (TBP)-associated factor, 32kDa, also known as TAF9, is a protein that in humans is encoded by the TAF9 gene.

<span class="mw-page-title-main">TAF4</span> Protein-coding gene in the species Homo sapiens

Transcription initiation factor TFIID subunit 4 is a protein that in humans is encoded by the TAF4 gene.

<span class="mw-page-title-main">TAF5</span> Protein-coding gene in the species Homo sapiens

Transcription initiation factor TFIID subunit 5 is a protein that in humans is encoded by the TAF5 gene.

<span class="mw-page-title-main">TAF11</span> Protein-coding gene in the species Homo sapiens

Transcription initiation factor TFIID subunit 11 also known as TAFII28, is a protein that in humans is encoded by the TAF11 gene.

<span class="mw-page-title-main">DRAP1</span> Protein-coding gene in the species Homo sapiens

Dr1-associated corepressor is a protein that in humans is encoded by the DRAP1 gene.

<span class="mw-page-title-main">Transcription factor IIIB 50 kDa subunit</span> Protein-coding gene in the species Homo sapiens

Transcription factor IIIB 50 kDa subunit (TFIIIB50) also known as b-related factor 2 (BRF-2) is a protein that in humans is encoded by the BRF2 gene.

RNA polymerase II holoenzyme is a form of eukaryotic RNA polymerase II that is recruited to the promoters of protein-coding genes in living cells. It consists of RNA polymerase II, a subset of general transcription factors, and regulatory proteins known as SRB proteins.

<span class="mw-page-title-main">B recognition element</span>

The B recognition element (BRE) is a DNA sequence found in the promoter region of most genes in eukaryotes and Archaea. The BRE is a cis-regulatory element that is found immediately near TATA box, and consists of 7 nucleotides. There are two sets of BREs: one (BREu) found immediately upstream of the TATA box, with the consensus SSRCGCC; the other (BREd) found around 7 nucleotides downstream, with the consensus RTDKKKK.

<span class="mw-page-title-main">TBP-associated factor</span> Protein domains

The TBP-associated factors (TAF) are proteins that associate with the TATA-binding protein in transcription initiation. It is a part of the transcription initiation factor TFIID multimeric protein complex. It also makes up many other factors, including SL1. They mediate the formation of the transcription preinitiation complex, a step preceding transcription of DNA to RNA by RNA polymerase II.

<span class="mw-page-title-main">Archaeal transcription factor B</span> Protein family

Archaeal transcription factor B is a protein family of extrinsic transcription factors that guide the initiation of RNA transcription in organisms that fall under the domain of Archaea. It is homologous to eukaryotic TFIIB and, more distantly, to bacterial sigma factor. Like these proteins, it is involved in forming transcription preinitiation complexes. Its structure includes several conserved motifs which interact with DNA and other transcription factors, notably the single type of RNA polymerase that performs transcription in Archaea.

References

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  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000028271 – Ensembl, May 2017
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  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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  6. ↑ Ha I, Lane WS, Reinberg D (August 1991). "Cloning of a human gene encoding the general transcription initiation factor IIB". Nature. 352 (6337): 689–95. Bibcode:1991Natur.352..689H. doi:10.1038/352689a0. PMID   1876184. S2CID   4267950.
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  8. ↑ Burton SP, Burton ZF (2014). "The σ enigma: bacterial σ factors, archaeal TFB and eukaryotic TFIIB are homologs". Transcription. 5 (4): e967599. doi:10.4161/21541264.2014.967599. PMC   4581349 . PMID   25483602.
  9. ↑ Tubon TC, Tansey WP, Herr W (April 2004). "A nonconserved surface of the TFIIB zinc ribbon domain plays a direct role in RNA polymerase II recruitment". Molecular and Cellular Biology. 24 (7): 2863–74. doi:10.1128/mcb.24.7.2863-2874.2004. PMC   371104 . PMID   15024075.
  10. ↑ Tang H, Sun X, Reinberg D, Ebright RH (February 1996). "Protein-protein interactions in eukaryotic transcription initiation: structure of the preinitiation complex". Proceedings of the National Academy of Sciences of the United States of America. 93 (3): 1119–24. Bibcode:1996PNAS...93.1119T. doi: 10.1073/pnas.93.3.1119 . PMC   40041 . PMID   8577725.
  11. 1 2 Bushnell DA, Westover KD, Davis RE, Kornberg RD (February 2004). "Structural basis of transcription: an RNA polymerase II-TFIIB cocrystal at 4.5 Angstroms". Science. 303 (5660): 983–8. Bibcode:2004Sci...303..983B. doi:10.1126/science.1090838. PMID   14963322. S2CID   36598301.
  12. ↑ Lagrange T, Kapanidis AN, Tang H, Reinberg D, Ebright RH (January 1998). "New core promoter element in RNA polymerase II-dependent transcription: sequence-specific DNA binding by transcription factor IIB". Genes & Development. 12 (1): 34–44. doi:10.1101/gad.12.1.34. PMC   316406 . PMID   9420329.
  13. ↑ Littlefield O, Korkhin Y, Sigler PB (November 1999). "The structural basis for the oriented assembly of a TBP/TFB/promoter complex". Proceedings of the National Academy of Sciences of the United States of America. 96 (24): 13668–73. Bibcode:1999PNAS...9613668L. doi: 10.1073/pnas.96.24.13668 . PMC   24122 . PMID   10570130.
  14. 1 2 3 4 5 Kostrewa D, Zeller ME, Armache KJ, Seizl M, Leike K, Thomm M, Cramer P (November 2009). "RNA polymerase II-TFIIB structure and mechanism of transcription initiation". Nature. 462 (7271): 323–30. Bibcode:2009Natur.462..323K. doi:10.1038/nature08548. hdl: 11858/00-001M-0000-0015-8570-1 . PMID   19820686. S2CID   205218821.
  15. 1 2 Sainsbury S, Niesser J, Cramer P (January 2013). "Structure and function of the initially transcribing RNA polymerase II-TFIIB complex". Nature. 493 (7432): 437–40. Bibcode:2013Natur.493..437S. doi:10.1038/nature11715. hdl: 11858/00-001M-0000-0015-3C83-A . PMID   23151482. S2CID   1711913.
  16. ↑ Weinzierl RO, Wiesler SC (2011). "Revealing the functions of TFIIB". Transcription. 2 (6): 254–7. doi:10.4161/trns.2.6.18076. PMC   3265785 . PMID   22223047.
  17. 1 2 Grünberg S, Hahn S (December 2013). "Structural insights into transcription initiation by RNA polymerase II". Trends in Biochemical Sciences. 38 (12): 603–11. doi:10.1016/j.tibs.2013.09.002. PMC   3843768 . PMID   24120742.
  18. ↑ He Y, Fang J, Taatjes DJ, Nogales E (March 2013). "Structural visualization of key steps in human transcription initiation". Nature. 495 (7442): 481–6. Bibcode:2013Natur.495..481H. doi:10.1038/nature11991. PMC   3612373 . PMID   23446344.
  19. ↑ Lee TI, Young RA (2000). "Transcription of eukaryotic protein-coding genes". Annual Review of Genetics. 34: 77–137. doi:10.1146/annurev.genet.34.1.77. PMID   11092823.
  20. ↑ Wang Y, Roberts SG (November 2010). "New insights into the role of TFIIB in transcription initiation". Transcription. 1 (3): 126–129. doi:10.4161/trns.1.3.12900. PMC   3023571 . PMID   21326885.
  21. 1 2 Gelev V, Zabolotny JM, Lange M, Hiromura M, Yoo SW, Orlando JS, Kushnir A, Horikoshi N, Paquet E, Bachvarov D, Schaffer PA, Usheva A (2014). "A new paradigm for transcription factor TFIIB functionality". Scientific Reports. 4: 3664. Bibcode:2014NatSR...4E3664G. doi:10.1038/srep03664. PMC   3895905 . PMID   24441171.
  22. ↑ Hahn S (November 2009). "Structural biology: New beginnings for transcription". Nature. 462 (7271): 292–3. Bibcode:2009Natur.462..292H. doi:10.1038/462292a. PMID   19924201. S2CID   205051031.
  23. ↑ Liu X, Bushnell DA, Kornberg RD (December 2011). "Lock and key to transcription: σ-DNA interaction". Cell. 147 (6): 1218–9. doi: 10.1016/j.cell.2011.11.033 . PMID   22153066.
  24. ↑ Friedman MJ, Shah AG, Fang ZH, Ward EG, Warren ST, Li S, Li XJ (December 2007). "Polyglutamine domain modulates the TBP-TFIIB interaction: implications for its normal function and neurodegeneration". Nature Neuroscience. 10 (12): 1519–28. doi:10.1038/nn2011. PMID   17994014. S2CID   8776470.
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