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The CTD code of RNA polymerase II: a structural view

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Abstract RNA polymerase II (RNA pol II) is not only the fundamental enzyme for gene expression but also the central coordinator of co‐transcriptional processing. RNA pol II associates with a large number of enzymes and protein/RNA‐binding factors through its C‐terminal domain (CTD) that consists of tandem repeats of the heptapeptide consensus Y1S2P3T4S5P6S7. The CTD is posttranslationally modified, yielding specific patterns (often called the CTD code) that are recognized by appropriate factors in coordination with the transcription cycle. Serine phosphorylations are currently the best characterized elements of the CTD code; however, the roles of the proline isomerization and other modifications of the CTD remain poorly understood. The dynamic remodeling of the CTD modifications by kinases, phosphatases, isomerases, and other enzymes introduce changes in the CTD structure and dynamics. These changes serve as structural switches that spatially and temporally regulate the binding of processing factors. Recent structural studies of the CTD bound to various proteins have revealed the basic rules that govern the recognition of these switches and shed light on the roles of these protein factors in the assemblies of the processing machineries. WIREs RNA 2013, 4:1–16. doi: 10.1002/wrna.1138 This article is categorized under: RNA Processing > Capping and 5' End Modifications RNA Processing > 3' End Processing RNA Processing > Processing of Small RNAs

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C‐terminal domain (CTD) recognition by capping enzymes. A close‐up view of the structure (a) of the Cgt1–CTD (PDB ID 1P16) and (b) of the MCE1–CTD complexes (PDB ID 3RTX). The CTD residues (yellow) are shown in stick representation in which the phosphate groups of Ser5 are shown in magenta, the serine–proline peptidyl–prolyl bonds are highlighted in blue, dashed lines indicate H‐bonds. Cgt1 is shown in electrostatic surface representation, MCE1 is shown in surface representation. The interacting residues of MCE1 (gray) are shown in stick representation. The primary sequences of the bound CTD are given below the corresponding structures in which blue boxes indicate residues involved in the intermolecular H‐bonds, red circles indicate other types of electrostatic interactions contributing to the binding. Alphabetical subscripts indicate the sequential number of the heptads.

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C‐terminal domain (CTD) recognition by SCP1. A close‐up of the structure of the SCP1–CTD complex (PBD ID 2GHT), where the CTD sequence and the critical Arg residue of SCP1 (gray) are shown in stick representation, SCP1 is shown in transparent surface representation. The phosphate group of the Ser5 residue is shown in magenta, the serine–proline peptidyl–prolyl bonds are highlighted in blue, black dashed lines indicate the intermolecular H‐bonds, red dashed lines indicate the intramolecular H‐bond. The primary sequence of the bound CTD is shown below the structure. Blue boxes indicate residues involved in the intermolecular H‐bonds, dashed line connects residues forming the intramolecular H‐bonds, red circles indicate other types of electrostatic interactions contributing to the binding, green asterisk indicates the phosphate group that coordinates Mg2+ ion.

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C‐terminal domain (CTD) recognition by the CTD‐interacting domain (CID) domains. (a) A close‐up of the CTD recognition by the SCAF8 CID (PDB ID 3D9L). (b) Schematic comparison of the CTD recognition by the CID domains of Pcf11 (PDB ID 1SZA), Rtt103 (PDB ID 2L0I), and SCAF8 (PDB ID 3D9P, 3D9O). (c) The structure of the Nrd1 CID–CTD complex (PBD ID 2lO6), the primary sequence of the bound peptide is given below the cartoon representation. (d) A close‐up of the pSer5 recognition by the Nrd1 CID. The CTD sequence and the critical Arg and Ser residues of the CIDs are shown in stick representation (in gray); the CIDs are shown in transparent cartoon representation. The CTD residues forming the β‐turn conformation are highlighted in orange, the phosphate group of Ser is shown in magenta, the serine–proline peptide bonds are highlighted in blue, and the dashed lines indicate H‐bonds. Blue boxes indicate residues involved in the intermolecular H‐bonds, dashes lines indicate residues forming the intramolecular H‐bonds, green asterisks indicate a direct recognition of the phosphorylated serine, red circles indicate other types of electrostatic interactions contributing to the binding. Alphabetical subscripts indicate the sequential number of the heptads.

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Diversity of the C‐terminal domain (CTD) backbone conformations. Cartoon representation of the CTD peptide (yellow) secondary structure upon binding with (a) Cgt1, (b) PIN1, (c) SCP1, (d) Ssu72, and (e) Rtt103 (PDB ID 1P16, 1F8A, 2GHQ, 3P9Y, and 2L0I, respectively). Primary sequence of the bound peptide is given below the cartoon representation, alphabetical subscripts indicate the sequential number of the heptads, the positions of the phosphorylated serine residue are shown in purple, asterisks indicate phosphate that is specifically recognized by the protein, the proline residues are shown in blue, cis and trans indicate the isomeric states of the serine–proline peptidyl–prolyl bonds. N, N‐terminal end; C, C‐terminal end.

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Example of modification patterns creating ‘the CTD code’ (C‐terminal domain). (a) Possible patterns of the serine phosphorylations within a single heptad repeat. (b) Possible patterns of the serine–proline peptidyl–prolyl bond isomerization within a single heptad repeat.

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Structural representation of the C‐terminal domain (CTD) heptad and its possible modifications. (a) Structural formula of the canonical heptapeptide of the CTD. (b) Representation of the serine phosphorylation. (c) Representation of the serine–proline peptidyl–prolyl bond isomerization. Small orange circles indicate hydroxyl group that can be phosphorylated or modified otherwise, big orange circle indicates phosphorylation, blue ellipses indicate the serine–proline peptidyl–prolyl bonds that can have two isomeric conformations, blue dashed lines show visual separation between amino acid residues.

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The C‐terminal domain (CTD) of RNA polymerase II. (a) The conservation of amino acid residues within the canonical heptad of the CTD. The amino acid sequences of the CTD from Sacchoromyces cerevisiae (shown are residues 1542–1723 from total 1733, UniProt ID P04050), Drosohila melanogaster (shown are residues 1598–1881 from total 1887, UniProt ID P04052), and Homo sapience (shown are residues 1593–1960 from total 1970, UniProt ID P24928). The amino acid residues shown in green do not possess the CTD consensus. Numbers on the left side indicate the sequential number of the heptads. (b) Schematic representation of RNA polymerase II largest subunit.

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C‐terminal domain (CTD) recognition by Ssu72. A close‐up of the fruit fly structure of the Ssu72–CTD complex (PBD ID 3P9Y) in which the CTD sequence (yellow) and the interacting amino acid residues of Ssu72 (gray) are shown in stick representation, Ssu72 is shown in surface representation. The phosphate group of Ser5 is shown in magenta, the serine–proline peptidyl–prolyl bonds are highlighted in blue, black dashed lines indicate the intermolecular H‐bonds, red dashed lines indicate the intramolecular H‐bond. The primary sequence of the bound CTD is shown below the structure in which blue boxes indicate residues involved in the intermolecular H‐bonds, dashes lines indicate residues involved in the intramolecular H‐bonds, red circles indicate other types of electrostatic interactions contributing to the binding. Alphabetical subscripts indicate the sequential number of the heptads.

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C‐terminal domain (CTD) recognition by the WW domain of human PIN1. A close‐up of the structure of the PIN1–CTD complex (PBD ID 1F8A) in which the CTD sequence (yellow) and the interacting amino acid residues of PIN1 (gray) are shown in stick representation, the WW domain of PIN1 is shown in cartoon representation. The phosphate groups of the phosphorylated Ser2 and Ser5 residues are shown in magenta, the serine–proline peptidyl–prolyl bonds are highlighted in blue, dashed lines indicate H‐bonds. The primary sequence of the bound CTD is shown below the structure in which blue boxes indicate residues involved in the intermolecular H‐bonds, red circles indicate other types of electrostatic interactions contributing to the binding. Alphabetical subscripts indicate the sequential number of the heptads.

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RNA Processing > Processing of Small RNAs
RNA Processing > Capping and 5′ End Modifications
RNA Processing > 3′ End Processing

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