A structural perspective of CTD function

Abstract

The C-terminal domain (CTD) of RNA polymerase II (Pol II) integrates nuclear events by binding proteins involved in mRNA biogenesis. CTD-binding proteins recognize a specific CTD phosphorylation pattern, which changes during the transcription cycle, due to the action of CTD-modifying enzymes. Structural and functional studies of CTD-binding and -modifying proteins now reveal some of the mechanisms underlying CTD function. Proteins recognize CTD phosphorylation patterns either directly, by contacting phosphorylated residues, or indirectly, without contact to the phosphate. The catalytic mechanisms of CTD kinases and phosphatases are known, but the basis for CTD specificity of these enzymes remains to be understood

Protein factors in pre-mRNA 3′-end processing

“…CTD peptides have also been observed in more extended conformations [209,210]. The variety of CTD conformations suggests that the CTD may not form a single basal structure [211].…”

Serine-7 but not serine-5 phosphorylation primes RNA polymerase II CTD for P-TEFb recognition

“…Release from this block requires the positive transcription elongation factor P-TEFb 2 , which is a heterodimer composed of the cyclin-dependent kinase Cdk9 and the regulatory subunit Cyclin T. P-TEFb mediates the transition from transcription initiation to productive elongation of pre-mRNA transcripts by phosphorylation of the carboxy-terminal domain (CTD) of the largest subunit of RNAPII. In humans, the CTD comprises 52 repeats of the consensus sequence Y 1 S 2 P 3 T 4 S 5 P 6 S 7 that exhibits only some variations from the strict consensus towards the C-terminus [3][4][5][6][7] . Phosphorylation of Ser5 by Cdk7 and Cdk8 kinases of TFIIH and the mediator complex, respectively, has been described to be concomitant with transcription initiation, whereas Cdk9 of P-TEFb is suggested to phosphorylate Ser2, which marks the elongation phase of transcription [3][4][5][6][7][8] .…”

“…In humans, the CTD comprises 52 repeats of the consensus sequence Y 1 S 2 P 3 T 4 S 5 P 6 S 7 that exhibits only some variations from the strict consensus towards the C-terminus [3][4][5][6][7] . Phosphorylation of Ser5 by Cdk7 and Cdk8 kinases of TFIIH and the mediator complex, respectively, has been described to be concomitant with transcription initiation, whereas Cdk9 of P-TEFb is suggested to phosphorylate Ser2, which marks the elongation phase of transcription [3][4][5][6][7][8] . In addition, Ser7 of the CTD can also be phosphorylated, which has been linked to small nuclear RNAs (snRNA) transcription and recruitment of the integrator complex [9][10][11][12][13] .…”

Transcriptional activators and activation mechanisms

“…The largest subunit of RNAP contains a tail-like structure known as the C-terminal domain (CTD), which is composed of heptapeptide repeats with a consensus of YSPTSPS (Meinhart et al, 2005). The number of heptapeptide repeats differs in different species; human RNAP has 52 such repeats whereas yeast RNAP has 26.…”

“…Heptapeptide repeats are subject to extensive phosphorylation. Importantly, the phosphorylation status and specificity exhibit dynamic changes as a function of the transcription cycle, reflective of the balanced action of site-specific kinases and phosphatases (Meinhart et al, 2005). During preinitiation complex formation, the CTD is un-phosphorylated.…”