The C-terminal domain (CTD) of human RNA polymerase II has 52 repeats of a similar heptapeptide sequence.

Will the RNA modification proteins only bind to some repeats at specific locations on this (e.g. the 1st repeat/the 10th repeat/the last repeat, etc), or will they bind randomly to any of the repeats?

If they bind to specific repeats, how can this specificity achieved?

If they bind to any of the repeats, then it would seem to me that several molecules of an RNA modification protein could be bound to a single RNA polymerase II CTD. Does this happen?

  • 2
    $\begingroup$ Part 2 last question. Lock and key is not the only mechanism for ligand recognition/binding. Induced fit models don't require fixed structures. In fact, the CTD is disordered. Also, please create separate questions for let's say protein binding, and then another for specificity. As it stands now, few would dare to undertake the monolithic task of answering this question. $\endgroup$
    – Roni Saiba
    Commented Nov 30, 2020 at 2:43
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    $\begingroup$ What research of your own have you done to try to answer this question? $\endgroup$
    – David
    Commented Nov 30, 2020 at 13:03
  • $\begingroup$ I've edited your question to clarify it a little etc. If I have changed your meaning, please say so and edit it accordingly. $\endgroup$
    – David
    Commented Dec 1, 2020 at 23:59
  • $\begingroup$ @David Wikipedia $\endgroup$
    – jw_
    Commented Dec 2, 2020 at 1:12
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    $\begingroup$ The entry in the Wikipedia article on RNA pol is just a couple of paras, and the references cited are all over ten years old. This tends to be the problem with Wikipedia — all entries are by individuals and after the first burst of enthusiasm people pass to other things and there is no incentive to maintain them. It's difficult if you haven't got access to a university library, but one needs to try harder for more recent review articles. $\endgroup$
    – David
    Commented Dec 2, 2020 at 15:05

1 Answer 1


In attempting to answer questions about protein structure, the first port of call (which one might expect the questioner to have also visited) is the Protein Data Bank — the global repository of such structures. There one can search for RNA Polymerase II CTD, look for complexes with other proteins, find recent publications in which they are reported, and consult them to find the state of knowledge of a topic.

Knowing nothing of the protein in question, I adopted this approach, and after looking at a few proteins and a few papers the following points seemed to emerge.

  • The CTD has a series of 7-amino acid (heptad) repeats — in mammals 21 of these are consensus(YSPTSPS), and 31 non-consensus (K7, rather than S7).
  • Further heterogeneity is afforded by phosphorylation (especially) and also glycosylation and proline isomerization, together with modification of the lysine of the non-consensus repeats.
  • It is thought that different post-transcriptional modifications are responsible for differential activation of 5′-capping or 3′-processing enzyme activities.
  • The CTD is disordered (unresolved) in the crystal structure of RNA Polymerase II, indicating that in the protein itself it does not adopt a fixed structure.
  • There are no structures of the CTD complexed to proteins it activates, so the question cannot be answered definitively.
  • There are structures of proteins complexed to short peptides (10- to 19-mers) based on the repeating sequence. These suggest that the structure of CTD in the complexes may be a spiral bound by specific interactions in a groove. The spiral formation may involve hydrogen-bonded β-turn motifs. A deduced structure from one such study with a 10mer is shown, together with indications of specific protein–protein interactions.

CTD-CID interaction

(Phosphorylated 10mer based on CTD complexed to the conserved CTD-interacting domain of mRNA processing factors RPRD1 and 2 — Adapted from Ni et al., Nature Structural and Molecular Biology (2014) 21, 686–695)

Concluding Remarks

The question contains two invalid assumptions — that proteins that interact with the CTD should interact with a single repeat, and that repeat should have a compact structure. Nevertheless, the functionality of the repeats and whether there are multiple interactions are valid questions. It appears from discussion in the paper by Ni et al. that the interacting unit is a 24-mer that binds to a dimer of the interacting protein (CID), and they propose that for phosphatases (and I presume protein kinases)15 molecules interact with the CTD at once.

What the situation is with 5′-capping or 3′-processing enzymes is another matter. There will only be one mRNA emerging from the RNA polymerase, so multiple binding would appear to make no sense. How much of the CTD is needed as rope to attach the processing enzyme soap? Does the soap slide along the rope? One would hope that eventually such questions would be answerable by molecular visualization techniques (see e.g. this BioRxiv preprint).

  • $\begingroup$ The question is asking about "repeat specificity" (i.e, will the binding of a specific protein on the CTD only happen on some specific repeat, or randoms on any repeat), not the specificity of the binding to a repeat. I'm not sure whether you get this? $\endgroup$
    – jw_
    Commented Dec 2, 2020 at 1:16
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    $\begingroup$ @jw_ David mentions that the structure of CTD complexed with its binding partners are not known (yet). In absence of this data the only way you can check specificity is by painstakingly deleting 51 repeats, while ensuring you maintain a similar conformation with the filler sequence you have entered. As you can see it is an extremely complicated thing to achieve. As such, I think this question is not likely to get a definite answer in the near future. $\endgroup$
    – Roni Saiba
    Commented Dec 2, 2020 at 2:01
  • $\begingroup$ @RoniSaiba I just realize that every result in biology come from real experiments (tons of work) $\endgroup$
    – jw_
    Commented Dec 2, 2020 at 2:23
  • $\begingroup$ @jw_ I live in a different time zone from you and posted without "wrapping my answer up", which I now have done. I believe it addresses your question. $\endgroup$
    – David
    Commented Dec 2, 2020 at 14:53

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