The Human EKC/KEOPS Complex Is Recruited to Cullin2 Ubiquitin Ligases by the Human Tumour Antigen PRAME

Costessi, Adalberto; Mahrour, Nawel; Sharma, Vikram; Stunnenberg, Rieka; Stoel, Marieke A.; Tijchon, Esther; Conaway, Joan Weliky; Conaway, Ronald C.; Stunnenberg, Hendrik G.

doi:10.1371/journal.pone.0042822

Cited by 44 publications

(45 citation statements)

References 35 publications

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“…The N 6 -threonylcarbamoyladenosine (t 6 A) modification is required for normal cell growth and accurate protein translation in bacteria, archaea, and eukaryotes. While the bacterial and lower eukaryotic components of the EKC/KEOPS complex are known, some of the human subunits are substantially diverged and have only recently been discovered [61, 62]. …”

Section: Resultsmentioning

confidence: 99%

“…Clear orthologs of four of these occur in humans and have previously been confirmed to participate in the EKC/KEOPS complex: TP53RK (the ortholog of Bud32, known to partially complement a Bud32 mutant [63]), TPRKB (the ortholog of Cgi121), LAGE3 (the ortholog of Pcc1), and OSGEP (the ortholog of Kae1). The yeast Gon7 has generally been thought to be fungi-specific [59, 61], and has no clear mammalian ortholog in major ortholog databases [36, 64]. …”

Section: Resultsmentioning

confidence: 99%

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Identifying direct contacts between protein complex subunits from their conditional dependence in proteomics datasets

et al. 2017

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Determining the three dimensional arrangement of proteins in a complex is highly beneficial for uncovering mechanistic function and interpreting genetic variation in coding genes comprising protein complexes. There are several methods for determining co-complex interactions between proteins, among them co-fractionation / mass spectrometry (CF-MS), but it remains difficult to identify directly contacting subunits within a multi-protein complex. Correlation analysis of CF-MS profiles shows promise in detecting protein complexes as a whole but is limited in its ability to infer direct physical contacts among proteins in sub-complexes. To identify direct protein-protein contacts within human protein complexes we learn a sparse conditional dependency graph from approximately 3,000 CF-MS experiments on human cell lines. We show substantial performance gains in estimating direct interactions compared to correlation analysis on a benchmark of large protein complexes with solved three-dimensional structures. We demonstrate the method’s value in determining the three dimensional arrangement of proteins by making predictions for complexes without known structure (the exocyst and tRNA multi-synthetase complex) and by establishing evidence for the structural position of a recently discovered component of the core human EKC/KEOPS complex, GON7/C14ORF142, providing a more complete 3D model of the complex. Direct contact prediction provides easily calculable additional structural information for large-scale protein complex mapping studies and should be broadly applicable across organisms as more CF-MS datasets become available.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Identifying direct contacts between protein complex subunits from their conditional dependence in proteomics datasets

et al. 2017

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“…The epitope tag (TY1-TY1-ER) had already been successfully used for IP and ChIP applications [25] and was placed at the N-terminus of the protein. TTE-MBD2 expressed in MCF-7 cells is specifically recognized by the Ty1 antibody (Fig1B left panel), that does not detect the endogenous protein in wild type MCF-7 cells (WT).…”

Section: Resultsmentioning

confidence: 99%

Genome-Wide Binding of MBD2 Reveals Strong Preference for Highly Methylated Loci

et al. 2014

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MBD2 is a subunit of the NuRD complex that is postulated to mediate gene repression via recruitment of the complex to methylated DNA. In this study we adopted an MBD2 tagging-approach to study its genome wide binding characteristics. We show that in vivo MBD2 is mainly recruited to CpG island promoters that are highly methylated. Interestingly, MBD2 binds around 1 kb downstream of the transcription start site of a subset of ∼400 CpG island promoters that are characterized by the presence of active histone marks, RNA polymerase II (Pol2) and low to medium gene expression levels and H3K36me3 deposition. These tagged-MBD2 binding sites in MCF-7 show increased methylation in a cohort of primary breast cancers but not in normal breast samples, suggesting a putative role for MBD2 in breast cancer.

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“…Costessi et al (2011, 2012) reported that PRAME is a component of Cullin2 based E3 ubiquitin ligase and is required to recruit Cullin2 ubiquitin ligase to the EKC/KEOPS complex. This complex is associated with the active promoters regulated by the nuclear transcription factor Y ( NFY ) [29], [32]. We hypothesize that PRAME also plays a role in spermatogenesis.…”

Section: Introductionmentioning

confidence: 99%

Differential Expression of PRAMEL1, a Cancer/Testis Antigen, during Spermatogenesis in the Mouse

et al. 2013

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PRAME belongs to a group of cancer/testis antigens (CTAs) that are characterized by their restricted expression in normal gametogenic tissues and a variety of tumors. The PRAME family is one of the most amplified gene families in the mouse and other mammalian genomes. Members of the PRAME gene family encode leucine-rich repeat (LRR) proteins functioning as transcription regulators in cancer cells. However, the role of PRAME in normal gonads is unknown. The objective of this study is to characterize the temporal and spatial expression of the mouse Pramel1 gene, and to determine the cellular localization of the PRAMEL1 protein during the mouse spermatogenesis. Our results indicated that the mouse Pramel1 was expressed in testis only. The mRNA and protein expression level was low in the newborn testes, and gradually increased from 1- to 3-week-old testes, and then remained constant after three weeks of age. Immunofluorescent staining on testis sections with the mouse PRAMEL1 antibody revealed that PRAMEL1 was localized in the cytoplasm of spermatocytes and the acrosomal region of round, elongating and elongated spermatids. Further analyses on the testis squash preparation and spermatozoa at a subcellular level indicated that the protein localization patterns of PRAMEL1 were coordinated with morphological alterations during acrosome formation in spermatids, and were significantly different in connecting piece, middle piece and principal piece of the flagellum between testicular and epididymal spermatozoa. Collectively, our results suggest that PRAMEL1 may play a role in acrosome biogenesis and sperm motility.

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The Human EKC/KEOPS Complex Is Recruited to Cullin2 Ubiquitin Ligases by the Human Tumour Antigen PRAME

Cited by 44 publications

References 35 publications

Identifying direct contacts between protein complex subunits from their conditional dependence in proteomics datasets

Identifying direct contacts between protein complex subunits from their conditional dependence in proteomics datasets

Genome-Wide Binding of MBD2 Reveals Strong Preference for Highly Methylated Loci

Differential Expression of PRAMEL1, a Cancer/Testis Antigen, during Spermatogenesis in the Mouse

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