5zyq | pdb_00005zyq

The Structure of Human PAF1/CTR9 complex

Structural highlights

5zyq is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Gene:	PAF1, PD2 (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[CTR9_HUMAN] Component of the PAF1 complex (PAF1C) which has multiple functions during transcription by RNA polymerase II and is implicated in regulation of development and maintenance of embryonic stem cell pluripotency. PAF1C associates with RNA polymerase II through interaction with POLR2A CTD non-phosphorylated and 'Ser-2'- and 'Ser-5'-phosphorylated forms and is involved in transcriptional elongation, acting both indepentently and synergistically with TCEA1 and in cooperation with the DSIF complex and HTATSF1. PAF1C is required for transcription of Hox and Wnt target genes. PAF1C is involved in hematopoiesis and stimulates transcriptional activity of KMT2A/MLL1; it promotes leukemogenesis through association with KMT2A/MLL1-rearranged oncoproteins, such as KMT2A/MLL1-MLLT3/AF9 and KMT2A/MLL1-MLLT1/ENL. PAF1C is involved in histone modifications such as ubiquitination of histone H2B and methylation on histone H3 'Lys-4' (H3K4me3). PAF1C recruits the RNF20/40 E3 ubiquitin-protein ligase complex and the E2 enzyme UBE2A or UBE2B to chromatin which mediate monoubiquitination of 'Lys-120' of histone H2B (H2BK120ub1); UB2A/B-mediated H2B ubiquitination is proposed to be coupled to transcription. PAF1C is involved in mRNA 3' end formation probably through association with cleavage and poly(A) factors. In case of infection by influenza A strain H3N2, PAF1C associates with viral NS1 protein, thereby regulating gene transcription. Required for mono- and trimethylation on histone H3 'Lys-4' (H3K4me3) and dimethylation on histone H3 'Lys-79' (H3K4me3). Required for Hox gene transcription. Required for the trimethylation of histone H3 'Lys-4' (H3K4me3) on genes involved in stem cell pluripotency; this function is synergistic with CXXC1 indicative for an involvement of the SET1 complex. Involved in transcriptional regulation of IL6-responsive genes and in JAK-STAT pathway; may regulate DNA-association of STAT3 (By similarity).^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7]

Publication Abstract from PubMed

The evolutionarily conserved multifunctional polymerase-associated factor 1 (Paf1) complex (Paf1C), which is composed of at least five subunits (Paf1, Leo1, Ctr9, Cdc73, and Rtf1), plays vital roles in gene regulation and has connections to development and human diseases. Here, we report two structures of each of the human and yeast Ctr9/Paf1 subcomplexes, which assemble into heterodimers with very similar conformations, revealing an interface between the tetratricopeptide repeat module in Ctr9 and Paf1. The structure of the Ctr9/Paf1 subcomplex may provide mechanistic explanations for disease-associated mutations in human PAF1 and CTR9. Our study reveals that the formation of the Ctr9/Paf1 heterodimer is required for the assembly of yeast Paf1C, and is essential for yeast viability. In addition, disruption of the interaction between Paf1 and Ctr9 greatly affects the level of histone H3 methylation in vivo. Collectively, our results shed light on Paf1C assembly and functional regulation.

Paf1 and Ctr9 subcomplex formation is essential for Paf1 complex assembly and functional regulation.,Xie Y, Zheng M, Chu X, Chen Y, Xu H, Wang J, Zhou H, Long J Nat Commun. 2018 Sep 18;9(1):3795. doi: 10.1038/s41467-018-06237-7. PMID:30228257^[8]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Zhu B, Mandal SS, Pham AD, Zheng Y, Erdjument-Bromage H, Batra SK, Tempst P, Reinberg D. The human PAF complex coordinates transcription with events downstream of RNA synthesis. Genes Dev. 2005 Jul 15;19(14):1668-73. PMID:16024656 doi:https://dx.doi.org/10.1101/gad.1292105
↑ Zhu B, Zheng Y, Pham AD, Mandal SS, Erdjument-Bromage H, Tempst P, Reinberg D. Monoubiquitination of human histone H2B: the factors involved and their roles in HOX gene regulation. Mol Cell. 2005 Nov 23;20(4):601-11. PMID:16307923 doi:https://dx.doi.org/S1097-2765(05)01646-1
↑ Ding L, Paszkowski-Rogacz M, Nitzsche A, Slabicki MM, Heninger AK, de Vries I, Kittler R, Junqueira M, Shevchenko A, Schulz H, Hubner N, Doss MX, Sachinidis A, Hescheler J, Iacone R, Anastassiadis K, Stewart AF, Pisabarro MT, Caldarelli A, Poser I, Theis M, Buchholz F. A genome-scale RNAi screen for Oct4 modulators defines a role of the Paf1 complex for embryonic stem cell identity. Cell Stem Cell. 2009 May 8;4(5):403-15. doi: 10.1016/j.stem.2009.03.009. Epub, 2009 Apr 2. PMID:19345177 doi:10.1016/j.stem.2009.03.009
↑ Chen Y, Yamaguchi Y, Tsugeno Y, Yamamoto J, Yamada T, Nakamura M, Hisatake K, Handa H. DSIF, the Paf1 complex, and Tat-SF1 have nonredundant, cooperative roles in RNA polymerase II elongation. Genes Dev. 2009 Dec 1;23(23):2765-77. doi: 10.1101/gad.1834709. PMID:19952111 doi:10.1101/gad.1834709
↑ Kim J, Guermah M, Roeder RG. The human PAF1 complex acts in chromatin transcription elongation both independently and cooperatively with SII/TFIIS. Cell. 2010 Feb 19;140(4):491-503. doi: 10.1016/j.cell.2009.12.050. PMID:20178742 doi:10.1016/j.cell.2009.12.050
↑ Muntean AG, Tan J, Sitwala K, Huang Y, Bronstein J, Connelly JA, Basrur V, Elenitoba-Johnson KS, Hess JL. The PAF complex synergizes with MLL fusion proteins at HOX loci to promote leukemogenesis. Cancer Cell. 2010 Jun 15;17(6):609-21. doi: 10.1016/j.ccr.2010.04.012. PMID:20541477 doi:10.1016/j.ccr.2010.04.012
↑ Nagaike T, Logan C, Hotta I, Rozenblatt-Rosen O, Meyerson M, Manley JL. Transcriptional activators enhance polyadenylation of mRNA precursors. Mol Cell. 2011 Feb 18;41(4):409-18. doi: 10.1016/j.molcel.2011.01.022. PMID:21329879 doi:10.1016/j.molcel.2011.01.022
↑ Xie Y, Zheng M, Chu X, Chen Y, Xu H, Wang J, Zhou H, Long J. Paf1 and Ctr9 subcomplex formation is essential for Paf1 complex assembly and functional regulation. Nat Commun. 2018 Sep 18;9(1):3795. doi: 10.1038/s41467-018-06237-7. PMID:30228257 doi:https://dx.doi.org/10.1038/s41467-018-06237-7

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OCA

[1] Zhu B, Mandal SS, Pham AD, Zheng Y, Erdjument-Bromage H, Batra SK, Tempst P, Reinberg D. The human PAF complex coordinates transcription with events downstream of RNA synthesis. Genes Dev. 2005 Jul 15;19(14):1668-73. PMID:16024656 doi:https://dx.doi.org/10.1101/gad.1292105

[2] Zhu B, Zheng Y, Pham AD, Mandal SS, Erdjument-Bromage H, Tempst P, Reinberg D. Monoubiquitination of human histone H2B: the factors involved and their roles in HOX gene regulation. Mol Cell. 2005 Nov 23;20(4):601-11. PMID:16307923 doi:https://dx.doi.org/S1097-2765(05)01646-1

[3] Ding L, Paszkowski-Rogacz M, Nitzsche A, Slabicki MM, Heninger AK, de Vries I, Kittler R, Junqueira M, Shevchenko A, Schulz H, Hubner N, Doss MX, Sachinidis A, Hescheler J, Iacone R, Anastassiadis K, Stewart AF, Pisabarro MT, Caldarelli A, Poser I, Theis M, Buchholz F. A genome-scale RNAi screen for Oct4 modulators defines a role of the Paf1 complex for embryonic stem cell identity. Cell Stem Cell. 2009 May 8;4(5):403-15. doi: 10.1016/j.stem.2009.03.009. Epub, 2009 Apr 2. PMID:19345177 doi:10.1016/j.stem.2009.03.009

[4] Chen Y, Yamaguchi Y, Tsugeno Y, Yamamoto J, Yamada T, Nakamura M, Hisatake K, Handa H. DSIF, the Paf1 complex, and Tat-SF1 have nonredundant, cooperative roles in RNA polymerase II elongation. Genes Dev. 2009 Dec 1;23(23):2765-77. doi: 10.1101/gad.1834709. PMID:19952111 doi:10.1101/gad.1834709

[5] Kim J, Guermah M, Roeder RG. The human PAF1 complex acts in chromatin transcription elongation both independently and cooperatively with SII/TFIIS. Cell. 2010 Feb 19;140(4):491-503. doi: 10.1016/j.cell.2009.12.050. PMID:20178742 doi:10.1016/j.cell.2009.12.050

[6] Muntean AG, Tan J, Sitwala K, Huang Y, Bronstein J, Connelly JA, Basrur V, Elenitoba-Johnson KS, Hess JL. The PAF complex synergizes with MLL fusion proteins at HOX loci to promote leukemogenesis. Cancer Cell. 2010 Jun 15;17(6):609-21. doi: 10.1016/j.ccr.2010.04.012. PMID:20541477 doi:10.1016/j.ccr.2010.04.012

[7] Nagaike T, Logan C, Hotta I, Rozenblatt-Rosen O, Meyerson M, Manley JL. Transcriptional activators enhance polyadenylation of mRNA precursors. Mol Cell. 2011 Feb 18;41(4):409-18. doi: 10.1016/j.molcel.2011.01.022. PMID:21329879 doi:10.1016/j.molcel.2011.01.022

[8] Xie Y, Zheng M, Chu X, Chen Y, Xu H, Wang J, Zhou H, Long J. Paf1 and Ctr9 subcomplex formation is essential for Paf1 complex assembly and functional regulation. Nat Commun. 2018 Sep 18;9(1):3795. doi: 10.1038/s41467-018-06237-7. PMID:30228257 doi:https://dx.doi.org/10.1038/s41467-018-06237-7

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5zyq | pdb_00005zyq

The Structure of Human PAF1/CTR9 complex

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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