TBP is a member of a small gene family of TBP-related factors.[6] The first TBP-related factor (TRF/TRF1) was identified in the fruit flyDrosophila, but appears to be fly or insect-specific. SubsequentlyTBPL1/TRF2 was found in the genomes of manymetazoans, whereasvertebrate genomes encode a third vertebrate family member,TBPL2/TRF3. In specific cell types or on specific promoters TBP can be replaced by one of these TBP-related factors, some of which interact with the TATA box similarly to TBP.
TBP is a subunit of the eukaryoticgeneral transcription factorTFIID. TFIID is the first protein to bind to DNA during the formation of thetranscription preinitiation complex ofRNA polymerase II (RNA Pol II).[7] As one of the few proteins in the preinitiation complex that binds DNA in a sequence-specific manner, it helps position RNA polymerase II over thetranscription start site of the gene. However, it is estimated that only 10–20% of human promoters have TATA boxes - the majority of human promoters areTATA-lesshousekeeping genepromoters - so TBP is probably not the only protein involved in positioning RNA polymerase II.. The binding of TBP to these promoters is facilitated by housekeeping gene regulators.[8][9] Interestingly, transcription initiates within a narrow region at around 30 bp downstream of TATA box on TATA-containing promoters,[10] while transcription start sites of TATA-less promoters are dispersed within a 200 bp region.[11][9]
Binding of TFIID to theTATA box in thepromoter region of the gene initiates the recruitment of other factors required for RNA Pol II to begin transcription. Some of the other recruited transcription factors includeTFIIA,TFIIB, andTFIIF. Each of these transcription factors contains several protein subunits.
TBP is also important for transcription byRNA polymerase I andRNA polymerase III, and is therefore involved in transcription initiation by all three RNA polymerases.[12]
TBP is involved inDNA melting (double strand separation) by bending theDNA by 80° (the AT-rich sequence to which it binds facilitates easy melting). The TBP is an unusual protein in that it binds the minor groove using a β sheet.
Another distinctive feature of TBP is a long string of glutamines in the N-terminus of the protein. This region modulates the DNA binding activity of the C-terminus, and modulation of DNA-binding affects the rate of transcription complex formation and initiation of transcription. Mutations that expand the number of CAG repeats encoding thispolyglutamine tract, and thus increase the length of the polyglutamine string, are associated withspinocerebellar ataxia 17, aneurodegenerative disorder classified as apolyglutamine disease.[13]
When TBP binds to aTATA box within theDNA, it distorts the DNA by inserting amino acid side-chains between base pairs, partially unwinding the helix, and doubly kinking it. The distortion is accomplished through a great amount of surface contact between the protein and DNA. TBP binds with the negatively charged phosphates in the DNA backbone through positively chargedlysine andarginine amino acid residues. The sharp bend in the DNA is produced through projection of four bulkyphenylalanine residues into the minor groove. As the DNA bends, its contact with TBP increases, thus enhancing the DNA-protein interaction.
The strain imposed on the DNA through this interaction initiates melting, or separation, of the strands. Because this region of DNA is rich inadenine andthymine residues, which base-pair through only twohydrogen bonds, the DNA strands are more easily separated. Separation of the two strands exposes the bases and allowsRNA polymerase II to begin transcription of thegene.
TBP's C-terminus composes of a helicoidal shape that (incompletely) complements the T-A-T-A region of DNA. This incompleteness allows DNA to be passively bent on binding.
The TATA-boxbindingprotein (TBP) is required for the initiation oftranscription by RNApolymerases I, II and III, frompromoters with or without a TATA box.[51][52] In the presence of a TATA-less promoter, TBP binds with the help of TBP-associated factors (TAFs).[53][54] TBP associates with a host of factors, including the generaltranscription factors TFIIA, -B, -D, -E, and -H, to form huge multi-subunit pre-initiation complexes on the corepromoter. Through its association with differenttranscription factors, TBP can initiatetranscription from different RNApolymerases. There are several related TBPs, including TBP-like (TBPL)proteins.[55]
^abcPointud JC, Mengus G, Brancorsini S, Monaco L, Parvinen M, Sassone-Corsi P, Davidson I (May 2003). "The intracellular localisation of TAF7L, a paralogue of transcription factor TFIID subunit TAF7, is developmentally regulated during male germ-cell differentiation".J. Cell Sci.116 (Pt 9):1847–58.doi:10.1242/jcs.00391.PMID12665565.S2CID24519687.
1c9b: CRYSTAL STRUCTURE OF A HUMAN TBP CORE DOMAIN-HUMAN TFIIB CORE DOMAIN COMPLEX BOUND TO AN EXTENDED, MODIFIED ADENOVIRAL MAJOR LATE PROMOTER (ADMLP)
1cdw: HUMAN TBP CORE DOMAIN COMPLEXED WITH DNA
1jfi: Crystal Structure of the NC2-TBP-DNA Ternary Complex
