Crystal structure of human DGCR8 core

Sohn, Sung-Hwa; Bae, Won Jin; Kim, Jeong Joo; Yeom, Kyu-Hyeon; Kim, V Narry; Cho, Yunje

doi:10.1038/nsmb1294

Cited by 106 publications

(136 citation statements)

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“…12,13,16 It independently binds to pri-miRNAs [17][18][19] and makes a major contribution to their recognition by the processing machinery. In addition, proper control of DGCR8 expression and activity appears to be important for normal miRNA biogenesis.…”

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confidence: 99%

Structure of the dimerization domain of DiGeorge Critical Region 8

et al. 2010

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Maturation of microRNAs (miRNAs,~22nt) from long primary transcripts [primary miRNAs (pri-miRNAs)] is regulated during development and is altered in diseases such as cancer. The first processing step is a cleavage mediated by the Microprocessor complex containing the Drosha nuclease and the RNA-binding protein DiGeorge critical region 8 (DGCR8). We previously reported that dimeric DGCR8 binds heme and that the heme-bound DGCR8 is more active than the heme-free form. Here, we identified a conserved dimerization domain in DGCR8. Our crystal structure of this domain (residues 298-352) at 1.7 Å resolution demonstrates a previously unknown use of a WW motif as a platform for extensive dimerization interactions. The dimerization domain of DGCR8 is embedded in an independently folded heme-binding domain and directly contributes to association with heme. Heme-binding-deficient DGCR8 mutants have reduced pri-miRNA processing activity in vitro. Our study provides structural and biochemical bases for understanding how dimerization and heme binding of DGCR8 may contribute to regulation of miRNA biogenesis.

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confidence: 99%

Structure of the dimerization domain of DiGeorge Critical Region 8

et al. 2010

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“…Alternatively, each dsRBD of DGCR8 could bind a single pri-miRNA simultaneously. This seems unlikely, as it would result in severe bending of the substrate, however, FRET studies have provided some evidence for this option [20]. Finally, larger assemblies could be generated by reciprocal binding of distinct pri-miRNAs to individual dsRBDs of the microprocessor.…”

Section: Hhmi Author Manuscriptmentioning

confidence: 99%

“…To date, several efforts have yielded biophysical and structural data on portions of the microprocessor complex [18][19][20]. The structure of Drosha's single dsRBD has been determined by NMR and modeled in complex with dsRNA [18].…”

Section: Microprocessormentioning

confidence: 99%

“…The stability of this complex is almost entirely driven by direct and water-mediated hydrogen-bonding interactions (PDBs: 3ADL [119] and 1DI2 [120]). b) The microprocessor complex (PDB: 2YT4 [20]) responsible for processing pri-miRNAs is comprised of the nucleases Drosha and DGCR8/Pasha. The crystal structure of the dsRBDs of human DGCR8 (pink/purple) suggests it recognizes dsRNA in the same manner as TRBP.…”

Section: Overview Of Effector Step Mechanismsmentioning

confidence: 99%

“…While there are nuances to the Drosha dsRBD structure that differentiate it from other dsRBDs, its structure is largely canonical and adopts the usual αβββα fold observed for other dsRBDs. Similarly for DGCR8, crystal structures of the dimerization domain and the tandem dsRBDs (dubbed the DGCR8 core) have been determined [19,20] (Fig. 1b).…”

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confidence: 99%

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From guide to target: molecular insights into eukaryotic RNA-interference machinery

Ipsaro

Joshua‐Tor

2015

Nat Struct Mol Biol

218

144

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Since its relatively recent discovery, RNA interference (RNAi) has emerged as a potent, specific, and ubiquitous means of gene regulation. Through a number of pathways that are conserved from yeast to humans, small non-coding RNAs direct molecular machinery to silence gene expression. In this review, we focus on mechanisms and structures that govern RNA silencing in higher organisms. In addition to highlighting recent advances, parallels and differences between RNAi pathways are discussed. Together, the studies reviewed herein reveal the versatility and programmability of RNA-induced Silencing Complexes (RISCs) and emphasize the importance of both upstream biogenesis and downstream silencing factors. Discovery and Biological Perspectives of RNA interferenceRNAi was first described by Fire and Mello in the 1990s when, in an attempt to use antisense RNA to down-regulate gene expression, they observed that double-stranded RNA (dsRNA) was more potent than sense or anti-sense RNA alone [1]. This seminal work boasted robust and specific gene knock down in addition to coining the term "RNA interference" (RNAi). Shortly beforehand, the discovery of individual regulatory RNAs in C. elegans hinted that small, non-coding RNAs might be a pervasive means of gene regulation in higher organisms [2,3]. In the following decade, with the mechanistic insight of Fire and Mello's work in hand, this idea was confirmed and it is now accepted that wellover 1,000 small RNAs are encoded in the human genome that may regulate over 60% of our genes [4,5]. It also became apparent that several seemingly disconnected phenomena are variations of RNAi-type pathways including co-suppression in plants, DNA elimination in Tetrahymena, and quelling in Neurospora [6]. The prevalence of RNAi is impressive and its importance is underscored by the fact that RNAi dysfunction is associated with numerous diseases and disorders including neurological maladies, cancers, and infertility.Shortly after the initial description of RNAi phenomenology, a burst of genetic, biochemical, biophysical, and bioinformatic efforts laid a strong foundation for identifying the molecular pathways, players, and parameters that govern silencing via RNAi. Work from Reprints and permissions information is available online at http://www.nature.com/reprints/index.html. HHMI Author ManuscriptHHMI Author Manuscript HHMI Author Manuscript numerous groups defined the molecular apparatus of RNAi as RISC (RNA-induced Silencing Complex), a ribonucleoprotein complex minimally comprised of a small singlestranded RNA (~20-31 nucleotides) and an Argonaute protein which serves as the effector molecule (reviewed in [7]). In this configuration, the loaded "guide" RNA acts as a specificity determinant that directs Argonaute and any other associated machinery to the target. The guide-loaded Argonaute platform underlies every example in the expansive array of known RNAi pathways in eukaryotes regardless of the source of the guide (structured loci, transposons, viral, etc.), the machinery ...

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Regulation of primary microRNA processing

2018

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Edited by Wilhelm JustMicroRNAs (miRNAs) are evolutionarily conserved small regulatory RNAs that participate in the adjustment of many, if not all, fundamental biological processes. Molecular mechanisms involved in miRNA biogenesis and mode of action have been elucidated in the past two decades. Similar to many cellular pathways, miRNA processing and function can be globally or specifically regulated at several levels and by numerous proteins and RNAs. Given their role as fine-tuning molecules, it is essential for miRNA expression to be tightly regulated in order to maintain cellular homeostasis. Here, we review our current knowledge of the first step of their maturation occurring in the nucleus and how it can be specifically and dynamically modulated.

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Crystal structure of human DGCR8 core

Cited by 106 publications

References 40 publications

Structure of the dimerization domain of DiGeorge Critical Region 8

Structure of the dimerization domain of DiGeorge Critical Region 8

From guide to target: molecular insights into eukaryotic RNA-interference machinery

Regulation of primary microRNA processing

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