Integrator complex

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<StructureSection load='7bv7' size='340' side='right' caption='Human integrator subunit 3 C-terminal dimer (grey, green) complex with subunit 6 C-terminal (pink) (PDB code [[7bv7]])' scene=''>
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<StructureSection load='7bv7' size='340' side='right' caption='Human integrator subunit 3 C-terminal dimer (cyan, green) complex with subunit 6 C-terminal (pink) (PDB code [[7bv7]])' scene='10/1043660/Cv/2'>
== Function ==
== Function ==
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'''Integrator complex''' (Int) is a protein complex which induces termination at loci transcribed by RNA polymerase II. Multiple Int subunits coordinate effective termination<ref>PMID:36634676</ref>. Int consists of 14 subunits some of which act as RNA endonuclease and are essential for small nuclear RNA biogenesis<ref>PMID:32800671</ref>. Int has protein phosphatase activity as well<ref>PMID:37995689</ref>..
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'''Integrator complex''' (Int) is a protein complex which induces termination at loci transcribed by RNA polymerase II. Multiple Int subunits coordinate effective termination<ref>PMID:36634676</ref>. Int consists of 14 subunits some of which act as RNA endonuclease and are essential for small nuclear RNA biogenesis<ref>PMID:32800671</ref>. Int has protein phosphatase activity as well<ref>PMID:37995689</ref>.
== Disease ==
== Disease ==
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== Structural highlights ==
== Structural highlights ==
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One of the pathways for fixing breaks n double-stranded DNA involve the participation of Int subunit 3 dimer and Int subunit 6. The 3D structure of the complex of the C-termini of Int3 dimer and Int6 shows the hydrophobic core interactions forming the Int3 dimer and the hydrophobic and ionic interactions between Int3 and Int6<ref>PMID:34400606</ref>.
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One of the pathways for fixing breaks in double-stranded DNA involve the participation of Int subunit 3 dimer and Int subunit 6. The 3D structure of the complex of the C-termini of Int3 dimer and Int6 shows the hydrophobic core interactions forming the Int3 dimer and the hydrophobic and ionic interactions between Int3 and Int6<ref>PMID:34400606</ref>.
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*Two Int3 protomers form a <scene name='10/1043660/Cv/4'>symmetrical dimer</scene> wherein two protomers are related by a non-crystallographic two-fold axis.
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*<scene name='10/1043660/Cv/8'>Whole dimer interface of Int3</scene>.
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*<scene name='10/1043660/Cv/13'>For simplicity of viewing, only few interactions involving Leu773, Gln774, Met782, Phe806, Tyr809, Leu845, Leu846, Gln871, and their dyad symmetry mates are shown at the dimer interface of Int3</scene>.
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*<scene name='10/1043660/Cv/11'>Whole Int3/Int6 interface</scene>.
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*<scene name='10/1043660/Cv/14'>The Int3/Int6 interface is composed of central hydrophobic residues, Pro823, Phe858 from Int6, and Phe806 from Int3</scene>. These hydrophobic interactions are further strengthened <scene name='10/1043660/Cv/17'> by salt bridges and hydrogen bonds</scene>.
==Integrator complex 3D structures==
==Integrator complex 3D structures==

Current revision

Human integrator subunit 3 C-terminal dimer (cyan, green) complex with subunit 6 C-terminal (pink) (PDB code 7bv7)

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References

  1. ↑ Wagner EJ, Tong L, Adelman K. Integrator is a global promoter-proximal termination complex. Mol Cell. 2023 Feb 2;83(3):416-427. PMID:36634676 doi:10.1016/j.molcel.2022.11.012
  2. ↑ Mendoza-Figueroa MS, Tatomer DC, Wilusz JE. The Integrator Complex in Transcription and Development. Trends Biochem Sci. 2020 Nov;45(11):923-934. PMID:32800671 doi:10.1016/j.tibs.2020.07.004
  3. ↑ Fujiwara R, Zhai SN, Liang D, Shah AP, Tracey M, Ma XK, Fields CJ, Mendoza-Figueroa MS, Meline MC, Tatomer DC, Yang L, Wilusz JE. IntS6 and the Integrator phosphatase module tune the efficiency of select premature transcription termination events. Mol Cell. 2023 Dec 21;83(24):4445-4460.e7. PMID:37995689 doi:10.1016/j.molcel.2023.10.035
  4. ↑ Oegema R, Baillat D, Schot R, van Unen LM, Brooks A, Kia SK, Hoogeboom AJM, Xia Z, Li W, Cesaroni M, Lequin MH, van Slegtenhorst M, Dobyns WB, de Coo IFM, van den Berg D, Verheijen FW, Kremer A, van der Spek PJ, Heijsman D, Wagner EJ, Fornerod M, Mancini GMS. Correction: Human mutations in integrator complex subunits link transcriptome integrity to brain development. PLoS Genet. 2017 Aug 1;13(8):e1006923. PMID:28763441 doi:10.1371/journal.pgen.1006923
  5. ↑ Mascibroda LG, Shboul M, Elrod ND, Colleaux L, Hamamy H, Huang KL, Peart N, Singh MK, Lee H, Merriman B, Jodoin JN, Sitaram P, Lee LA, Fathalla R, Al-Rawashdeh B, Ababneh O, El-Khateeb M, Escande-Beillard N, Nelson SF, Wu Y, Tong L, Kenney LJ, Roy S, Russell WK, Amiel J, Reversade B, Wagner EJ. INTS13 variants causing a recessive developmental ciliopathy disrupt assembly of the Integrator complex. Nat Commun. 2022 Oct 13;13(1):6054. PMID:36229431 doi:10.1038/s41467-022-33547-8
  6. ↑ Jia Y, Cheng Z, Bharath SR, Sun Q, Su N, Huang J, Song H. Crystal structure of the INTS3/INTS6 complex reveals the functional importance of INTS3 dimerization in DSB repair. Cell Discov. 2021 Aug 17;7(1):66. doi: 10.1038/s41421-021-00283-0. PMID:34400606 doi:http://dx.doi.org/10.1038/s41421-021-00283-0

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