Structure of the RBM7–ZCCHC8 core of the NEXT complex reveals connections to splicing factors

Falk, Sebastian; Finogenova, Ksenia; Melko, Mireille; Benda, Christian; Lykke‐Andersen, Søren; Jensen, Torben Heick; Conti, Elena

doi:10.1038/ncomms13573

Cited by 40 publications

(52 citation statements)

References 55 publications

(83 reference statements)

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“…Our interface is similar to that recently observed in the RBM7-ZCCHC8 structure ( Fig. 3; Falk et al 2016). It was suggested that the mutually exclusive interaction of RBM7 with ZCCHC8 and SAP145…”

Section: Discussionsupporting

confidence: 91%

“…Apart from the conserved tryptophan, our structure lacks the other important UHM-ULM features. Instead, it represents a recently discovered novel type of RRM protein interaction (Falk et al 2016). In our structure an extensive and conserved hydrophobic interface is present.…”

Section: Discussionmentioning

confidence: 92%

“…Recently, the structure of the complex of exosomal accessory factors RBM7 and ZCCHC8 proline-rich region was published (Falk et al 2016). These proteins together with hMTR4 form the nuclear exosome targeting (NEXT) complex.…”

Section: Similarities To Other Structuresmentioning

confidence: 99%

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Crystal structure of U2 snRNP SF3b components: Hsh49p in complex with Cus1p-binding domain

Roon¹,

Oubridge²,

Obayashi³

et al. 2017

RNA

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Spliceosomal proteins Hsh49p and Cus1p are components of SF3b, which together with SF3a, Msl1p/Lea1p, Sm proteins, and U2 snRNA, form U2 snRNP, which plays a crucial role in pre-mRNA splicing. Hsh49p, comprising two RRMs, forms a heterodimer with Cus1p. We determined the crystal structures of Saccharomyces cerevisiae full-length Hsh49p as well as its RRM1 in complex with a minimal binding region of Cus1p (residues 290-368). The structures show that the Cus1 fragment binds to the α-helical surface of Hsh49p RRM1, opposite the four-stranded β-sheet, leaving the canonical RNA-binding surface available to bind RNA. Hsh49p binds the 5 ′ end region of U2 snRNA via RRM1. Its affinity is increased in complex with Cus1(290-368)p, partly because an extended RNA-binding surface forms across the protein-protein interface. The Hsh49p RRM1-Cus1(290-368)p structure fits well into cryo-EM density of the B act spliceosome, corroborating the biological relevance of our crystal structure.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 92%

See 1 more Smart Citation

Crystal structure of U2 snRNP SF3b components: Hsh49p in complex with Cus1p-binding domain

Roon¹,

Oubridge²,

Obayashi³

et al. 2017

RNA

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show abstract

“…The NEXT complex promotes degradation of PROMPTs and 3 ′ extended RNAs, including aberrant hTR, in the nucleoplasm (Preker et al 2008;Lubas et al 2011;Tseng et al 2015). A recent study showed that ZCCHC8 interacts with the RNA recognition motif (RRM) domain of RBM7 via a proline-rich sequence and bridges interactions with MTR4 in the complex (Falk et al 2016). PAXT promotes degradation of longer and more mature [with respect to poly(A) tail length] substrates compared with NEXT substrates (Meola et al 2016).…”

Section: Cofactor-mediated Bridging To the Cap-binding Complexmentioning

confidence: 99%

Targeting RNA for processing or destruction by the eukaryotic RNA exosome and its cofactors

2017

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The eukaryotic RNA exosome is an essential and conserved protein complex that can degrade or process RNA substrates in the 3 ′ -to-5 ′ direction. Since its discovery nearly two decades ago, studies have focused on determining how the exosome, along with associated cofactors, achieves the demanding task of targeting particular RNAs for degradation and/or processing in both the nucleus and cytoplasm. In this review, we highlight recent advances that have illuminated roles for the RNA exosome and its cofactors in specific biological pathways, alongside studies that attempted to dissect these activities through structural and biochemical characterization of nuclear and cytoplasmic RNA exosome complexes.

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“…In addition, the RBM7 RRM contains a proline-rich region that not only directly interacts with ZCCHC8 ( Fig. 3B), but also, in a mutually exclusive manner, binds to SAP145, a spliceosomal SF3b complex component, providing a potential mechanism for how the NEXT complex recognizes intronic RNAs (Falk et al 2016).…”

Section: Exosome Cofactor Gene Mutations Rbm7mentioning

confidence: 99%

The RNA exosome and RNA exosome-linked disease

Morton

Kuiper

Jones

et al. 2017

RNA

119

124

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The RNA exosome is an evolutionarily conserved, ribonuclease complex that is critical for both processing and degradation of a variety of RNAs. Cofactors that associate with the RNA exosome likely dictate substrate specificity for this complex. Recently, mutations in genes encoding both structural subunits of the RNA exosome and its cofactors have been linked to human disease. Mutations in the RNA exosome genes and cause pontocerebellar hypoplasia type 1b (PCH1b) and type 1c (PCH1c), respectively, which are similar autosomal-recessive, neurodegenerative diseases. Mutations in the RNA exosome gene cause a distinct syndrome with various tissue-specific phenotypes including retinitis pigmentosa and mild intellectual disability. Mutations in genes that encode RNA exosome cofactors also cause tissue-specific diseases with complex phenotypes. How mutations in these genes give rise to distinct, tissue-specific diseases is not clear. In this review, we discuss the role of the RNA exosome complex and its cofactors in human disease, consider the amino acid changes that have been implicated in disease, and speculate on the mechanisms by which exosome gene mutations could underlie dysfunction and disease.

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Structure of the RBM7–ZCCHC8 core of the NEXT complex reveals connections to splicing factors

Cited by 40 publications

References 55 publications

Crystal structure of U2 snRNP SF3b components: Hsh49p in complex with Cus1p-binding domain

Crystal structure of U2 snRNP SF3b components: Hsh49p in complex with Cus1p-binding domain

Targeting RNA for processing or destruction by the eukaryotic RNA exosome and its cofactors

The RNA exosome and RNA exosome-linked disease

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