Crystal Structure of the C-Terminal Domain of Human DPY-30-Like Protein: A Component of the Histone Methyltransferase Complex

Wang, Xianping; Lou, Zhiyong; Dong, Xinhong; Yang, Wen; Peng, Yong; Yin, Bin; Gong, Yanhua; Yuan, Jing; Zhou, Weihong; Bartlam, Mark; Peng, Xiaozhong; Rao, Zihe

doi:10.1016/j.jmb.2009.05.061

Cited by 35 publications

(54 citation statements)

References 25 publications

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“…These residues are located in the first predicted ␣-helix of the Dpy-30 domain of Sdc1. Interestingly, based on the x-ray crystal structure of the human Dpy-30 domain of DPY-30, it has been suggested that these two conserved leucine residues are probably forming a putative binding pocket (45). Similar to deletions within the predicted ␣-helix, all Sdc1 Leu-134 and Leu-135 mutations (Sdc1 L134E,L135E, Sdc1 L134A,L135A, and Sdc1 L134I, L135I) disrupted binding to Bre2, suggesting that the Dpy-30 domain of Sdc1 might be sufficient to mediate binding to Bre2 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In addition, the DPY-30 crystal structure was solved as a dimer, and RIIa domains have also been shown to dimerize; therefore, we sought to determine if bacterially expressed Sdc1 can dimerize in vitro (41,43,45). Interestingly, Sdc1 dimers were detected on non-reducing polyacrylamide gels and disrupted in the presence of the sulfhydryl-reducing agent ␤-mercaptoethanol, suggesting that a cysteine residue is mediating this event (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Because all mutations within the Dpy-30 domain of Sdc1 disrupted interaction with Bre2, it is likely that the overall structure of the Dpy-30 domain is important for interacting with the C terminus of Bre2. Interestingly, during preparation of this manuscript, the x-ray crystal structure of the Dpy-30 domain of human DPY-30 was solved (45). The structure indicates that the human DPY-30 domain can form a four-helix bundle.…”

Section: Discussionmentioning

confidence: 99%

“…The structure indicates that the human DPY-30 domain can form a four-helix bundle. Based on the human crystal structure and structure prediction analysis of yeast Sdc1, it appears that deletions of the PXXP motif or mutations that change the prolines to alanines are within a loop region connecting two ␣-helices (45,51). Therefore, it is likely that this loop is important for the overall structure or position of the two ␣-helices.…”

Section: Discussionmentioning

confidence: 99%

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A Conserved Interaction between the SDI Domain of Bre2 and the Dpy-30 Domain of Sdc1 Is Required for Histone Methylation and Gene Expression

South¹,

Fingerman

Mersman

et al. 2010

Journal of Biological Chemistry

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In Saccharomyces cerevisiae, lysine 4 on histone H3 (H3K4) is methylated by the Set1 complex (Set1C or COMPASS). Besides the catalytic Set1 subunit, several proteins that form the Set1C (Swd1, Swd2, Swd3, Spp1, Bre2, and Sdc1) are also needed to mediate proper H3K4 methylation. Until this study, it has been unclear how individual Set1C members interact and how this interaction may impact histone methylation and gene expression. In this study, Bre2 and Sdc1 are shown to directly interact, and it is shown that the association of this heteromeric complex is needed for proper H3K4 methylation and gene expression to occur. Interestingly, mutational and biochemical analysis identified the C terminus of Bre2 as a critical protein-protein interaction domain that binds to the Dpy-30 domain of Sdc1. Using the human homologs of Bre2 and Sdc1, ASH2L and DPY-30, respectively, we demonstrate that the C terminus of ASH2L also interacts with the Dpy-30 domain of DPY-30, suggesting that this protein-protein interaction is maintained from yeast to humans. Because of the functionally conserved nature of the C terminus of Bre2 and ASH2L, this region was named the SDI (Sdc1 Dpy-30 interaction) domain. Finally, we show that the SDI-Dpy-30 domain interaction is physiologically important for the function of Set1 in vivo, because specific disruption of this interaction prevents Bre2 and Sdc1 association with Set1, resulting in H3K4 methylation defects and decreases in gene expression. Overall, these and other mechanistic studies on how H3K4 methyltransferase complexes function will likely provide insights into how human MLL and SET1-like complexes or overexpression of ASH2L leads to oncogenesis.In Saccharomyces cerevisiae, histone H3 lysine 4 (H3K4) 3 mono-, di-, and trimethylation is mediated by the Set1 histone methyltransferase (1, 2). Set1 and H3K4 methylation were first identified to be required for silencing at rDNA, telomeres, and mating-type loci (3-6). Set1 and H3K4 trimethylation are also found to be located at euchromatin and enriched in the 5Ј-ends of coding regions of transcriptionally active genes (7,8). In addition, Set1 and its human homologs, MLL1, MLL2, and hSET1, associate with the phosphorylated C-terminal domain of RNA polymerase II (7, 9 -11). More recently, it has been shown that various chromodomain and PHD zinc finger-containing proteins can bind to histones and H3K4 di-and trimethylated histone peptides and histones (12)(13)(14). Therefore, these and other studies suggest that Set1-mediated histone methylation plays a positive role in mediating gene expression through recruitment of effector proteins.Unlike other yeast histone methyltransferases, Set1 requires a multiprotein complex for its activity in vitro and in vivo (1,(15)(16)(17)(18). The yeast Set1 complex, also called Set1C or COMPASS (complex associated with Set1), consists of eight subunits (Set1, Bre2, Sdc1, Swd1, Swd2, Swd3, Spp1, and Shg1) (15,18,19). After the discovery of yeast Set1C, it was determined that the human H3K4 methyltransferases MLL1 ...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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A Conserved Interaction between the SDI Domain of Bre2 and the Dpy-30 Domain of Sdc1 Is Required for Histone Methylation and Gene Expression

South¹,

Fingerman

Mersman

et al. 2010

Journal of Biological Chemistry

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“…Although Ash2L 510-523 was included in the crystallization construct of Ash2L SPRY , residues 510-523 are not visible in the electron-density map, indicating that the Ash-2L DBM peptide is not part of the compact SPRY domain. DPY30 DD adopts a canonical four-helix-bundle conformation with extensive hydrophobic surface [9]. The structure of DPY30 DD is similar to that of PKA RIIa, the RIIa isoform of a cAMP-dependent protein kinase [10].…”

Section: Dear Editormentioning

confidence: 93%

Structure of the SPRY domain of human Ash2L and its interactions with RbBP5 and DPY30

et al. 2012

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Single cell transcriptomes of normal endometrial derived organoids uncover novel cell type markers and cryptic differentiation of primary tumours

Cochrane

Campbell

Greening

et al. 2020

The Journal of Pathology

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Endometrial carcinoma, the most common gynaecological cancer, develops from endometrial epithelium which is composed of secretory and ciliated cells. Pathologic classification is unreliable and there is a need for prognostic tools. We used single cell sequencing to study organoid model systems derived from normal endometrial endometrium to discover novel markers specific for endometrial ciliated or secretory cells. A marker of secretory cells (MPST) and several markers of ciliated cells (FAM92B, WDR16, and DYDC2) were validated by immunohistochemistry on organoids and tissue sections. We performed single cell sequencing on endometrial and ovarian tumours and found both secretory‐like and ciliated‐like tumour cells. We found that ciliated cell markers (DYDC2, CTH, FOXJ1, and p73) and the secretory cell marker MPST were expressed in endometrial tumours and positively correlated with disease‐specific and overall survival of endometrial cancer patients. These findings suggest that expression of differentiation markers in tumours correlates with less aggressive disease, as would be expected for tumours that retain differentiation capacity, albeit cryptic in the case of ciliated cells. These markers could be used to improve the risk stratification of endometrial cancer patients, thereby improving their management. We further assessed whether consideration of MPST expression could refine the ProMiSE molecular classification system for endometrial tumours. We found that higher expression levels of MPST could be used to refine stratification of three of the four ProMiSE molecular subgroups, and that any level of MPST expression was able to significantly refine risk stratification of the copy number high subgroup which has the worst prognosis. Taken together, this shows that single cell sequencing of putative cells of origin has the potential to uncover novel biomarkers that could be used to guide management of cancers. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Crystal Structure of the C-Terminal Domain of Human DPY-30-Like Protein: A Component of the Histone Methyltransferase Complex

Cited by 35 publications

References 25 publications

A Conserved Interaction between the SDI Domain of Bre2 and the Dpy-30 Domain of Sdc1 Is Required for Histone Methylation and Gene Expression

A Conserved Interaction between the SDI Domain of Bre2 and the Dpy-30 Domain of Sdc1 Is Required for Histone Methylation and Gene Expression

Structure of the SPRY domain of human Ash2L and its interactions with RbBP5 and DPY30

Single cell transcriptomes of normal endometrial derived organoids uncover novel cell type markers and cryptic differentiation of primary tumours

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