| Structural highlights
6rr0 is a 14 chain structure with sequence from Atcc 18824. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | |
| NonStd Res: | |
| Related: | 6qsz, 6qtm |
| Gene: | SIR4, ASD1, STE9, UTH2, YDR227W, YD9934.12 (ATCC 18824) |
| Activity: | Ubiquitinyl hydrolase 1, with EC number 3.4.19.12 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[SIR4_YEAST] The proteins SIR1 through SIR4 are required for transcriptional repression of the silent mating type loci, HML and HMR. The proteins SIR2 through SIR4 repress mulitple loci by modulating chromatin structure. Involves the compaction of chromatin fiber into a more condensed form.[1] [UBP10_YEAST] Deubiquitinating enzyme involved in telomere and HM loci silencing, which is the repression of chromatin structure which leads to a stop in the transcription of nearby genes (PubMed:9755194, PubMed:10490600, PubMed:14623890). Targets histone H2B for deubiquitination, thus helping to localize SIR2 to the telomere (PubMed:15721261, PubMed:17028327, PubMed:22056669). At silent chromatin, including telomeres and the rDNA locus, not only maintains low H2B 'Lys-123' ubiquitination (H2BK123Ub), but also low H3 'Lys-4' and 'Lys-79' methylation (H3K4me and H3K79me, respectively) (PubMed:15721261, PubMed:15988024). Controls the proliferating-cell nuclear antigen PCNA/POL30 deubiquitination which is crucial for keeping TLS polymerases in check as well as for down-regulating the error-free bypass (PubMed:22829782). Deubiquitinates and stabilizes RPA190, the largest subunit of RNA polymerase I, to achieve optimal levels of ribosomes and cell growth (PubMed:22902402). Protects also nutrient transporters such as GAP1 from ubiquitin-dependent endocytosis (PubMed:11352638).[2] [3] [4] [5] [6] [7] [8] [9] [10] [11]
Publication Abstract from PubMed
In Saccharomyces cerevisiae, the silent information regulator (SIR) proteins Sir2/3/4 form a complex that suppresses transcription in subtelomeric regions and at the homothallic mating-type (HM) loci. Here, we identify a non-canonical BRCA1 C-terminal domain (H-BRCT) in Sir4, which is responsible for tethering telomeres to the nuclear periphery. We show that Sir4 H-BRCT and the closely related Dbf4 H-BRCT serve as selective phospho-epitope recognition domains that bind to a variety of phosphorylated target peptides. We present detailed structural information about the binding mode of established Sir4 interactors (Esc1, Ty5, Ubp10) and identify several novel interactors of Sir4 H-BRCT, including the E3 ubiquitin ligase Tom1. Based on these findings, we propose a phospho-peptide consensus motif for interaction with Sir4 H-BRCT and Dbf4 H-BRCT. Ablation of the Sir4 H-BRCT phospho-peptide interaction disrupts SIR-mediated repression and perinuclear localization. In conclusion, the Sir4 H-BRCT domain serves as a hub for recruitment of phosphorylated target proteins to heterochromatin to properly regulate silencing and nuclear order.
The Sir4 H-BRCT domain interacts with phospho-proteins to sequester and repress yeast heterochromatin.,Deshpande I, Keusch JJ, Challa K, Iesmantavicius V, Gasser SM, Gut H EMBO J. 2019 Oct 15;38(20):e101744. doi: 10.15252/embj.2019101744. Epub 2019 Sep , 12. PMID:31515872[12]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Bupp JM, Martin AE, Stensrud ES, Jaspersen SL. Telomere anchoring at the nuclear periphery requires the budding yeast Sad1-UNC-84 domain protein Mps3. J Cell Biol. 2007 Dec 3;179(5):845-54. Epub 2007 Nov 26. PMID:18039933 doi:http://dx.doi.org/10.1083/jcb.200706040
- ↑ Kahana A, Gottschling DE. DOT4 links silencing and cell growth in Saccharomyces cerevisiae. Mol Cell Biol. 1999 Oct;19(10):6608-20. doi: 10.1128/mcb.19.10.6608. PMID:10490600 doi:http://dx.doi.org/10.1128/mcb.19.10.6608
- ↑ Kahana A. The deubiquitinating enzyme Dot4p is involved in regulating nutrient uptake. Biochem Biophys Res Commun. 2001 Apr 13;282(4):916-20. doi:, 10.1006/bbrc.2001.4669. PMID:11352638 doi:http://dx.doi.org/10.1006/bbrc.2001.4669
- ↑ Orlandi I, Bettiga M, Alberghina L, Vai M. Transcriptional profiling of ubp10 null mutant reveals altered subtelomeric gene expression and insurgence of oxidative stress response. J Biol Chem. 2004 Feb 20;279(8):6414-25. doi: 10.1074/jbc.M306464200. Epub 2003, Nov 17. PMID:14623890 doi:http://dx.doi.org/10.1074/jbc.M306464200
- ↑ Emre NC, Ingvarsdottir K, Wyce A, Wood A, Krogan NJ, Henry KW, Li K, Marmorstein R, Greenblatt JF, Shilatifard A, Berger SL. Maintenance of low histone ubiquitylation by Ubp10 correlates with telomere-proximal Sir2 association and gene silencing. Mol Cell. 2005 Feb 18;17(4):585-94. doi: 10.1016/j.molcel.2005.01.007. PMID:15721261 doi:http://dx.doi.org/10.1016/j.molcel.2005.01.007
- ↑ Gardner RG, Nelson ZW, Gottschling DE. Ubp10/Dot4p regulates the persistence of ubiquitinated histone H2B: distinct roles in telomeric silencing and general chromatin. Mol Cell Biol. 2005 Jul;25(14):6123-39. doi: 10.1128/MCB.25.14.6123-6139.2005. PMID:15988024 doi:http://dx.doi.org/10.1128/MCB.25.14.6123-6139.2005
- ↑ Calzari L, Orlandi I, Alberghina L, Vai M. The histone deubiquitinating enzyme Ubp10 is involved in rDNA locus control in Saccharomyces cerevisiae by affecting Sir2p association. Genetics. 2006 Dec;174(4):2249-54. doi: 10.1534/genetics.106.063099. Epub 2006, Oct 8. PMID:17028327 doi:http://dx.doi.org/10.1534/genetics.106.063099
- ↑ Schulze JM, Hentrich T, Nakanishi S, Gupta A, Emberly E, Shilatifard A, Kobor MS. Splitting the task: Ubp8 and Ubp10 deubiquitinate different cellular pools of H2BK123. Genes Dev. 2011 Nov 1;25(21):2242-7. doi: 10.1101/gad.177220.111. PMID:22056669 doi:http://dx.doi.org/10.1101/gad.177220.111
- ↑ Gallego-Sanchez A, Andres S, Conde F, San-Segundo PA, Bueno A. Reversal of PCNA ubiquitylation by Ubp10 in Saccharomyces cerevisiae. PLoS Genet. 2012;8(7):e1002826. doi: 10.1371/journal.pgen.1002826. Epub 2012 Jul , 19. PMID:22829782 doi:http://dx.doi.org/10.1371/journal.pgen.1002826
- ↑ Richardson LA, Reed BJ, Charette JM, Freed EF, Fredrickson EK, Locke MN, Baserga SJ, Gardner RG. A conserved deubiquitinating enzyme controls cell growth by regulating RNA polymerase I stability. Cell Rep. 2012 Aug 30;2(2):372-85. doi: 10.1016/j.celrep.2012.07.009. Epub 2012, Aug 16. PMID:22902402 doi:http://dx.doi.org/10.1016/j.celrep.2012.07.009
- ↑ Singer MS, Kahana A, Wolf AJ, Meisinger LL, Peterson SE, Goggin C, Mahowald M, Gottschling DE. Identification of high-copy disruptors of telomeric silencing in Saccharomyces cerevisiae. Genetics. 1998 Oct;150(2):613-32. PMID:9755194
- ↑ Deshpande I, Keusch JJ, Challa K, Iesmantavicius V, Gasser SM, Gut H. The Sir4 H-BRCT domain interacts with phospho-proteins to sequester and repress yeast heterochromatin. EMBO J. 2019 Oct 15;38(20):e101744. doi: 10.15252/embj.2019101744. Epub 2019 Sep , 12. PMID:31515872 doi:http://dx.doi.org/10.15252/embj.2019101744
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