Common Design Principles in the Spliceosomal RNA Helicase Brr2 and in the Hel308 DNA Helicase

Peña, Vladimir; Mozaffari‐Jovin, Sina; Fabrizio, Patrizia; Orłowski, Jerzy; Bujnicki, Janusz M.; Lührmann, Reinhard; Wahl, Markus C.

doi:10.1016/j.molcel.2011.01.018

Cited by 18 publications

(59 citation statements)

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“…The sequence identity between the target and the template was 28%, a bit higher than average 25% sequence identity of many helicase superfamily members. From model it shows that hBrr2 (residues 477–1174) folds into five domains (RecA-like 1 and 2 domains, helical bundle, HLH and WH domains) [16] and possesses a hole at the center of molecule (Figure 5A), similar to that of Hel308-DNA complex [17] (Figure 5B). Three conserved amino acids across different species, highlighted as Q885, S1087 and R1090 of hBrr2 are shown as space-filling spheres (Figure 5A) in the model.…”

Section: Resultsmentioning

confidence: 98%

“…hBrr2 is a core component of U4/U6-U5 snRNPs and catalyzes unwinding of the U4/U6 snRNP duplex, which is a key step in the catalytic activation of the spliceosome [19], [20]. The protein is homologous to yest Brr2 and belongs to the DExD/H box protein family and possesses two consecutive Hel308-like modules (Hel308-1 and Hel308-2), each with a DExD/H box domain with ATPase activity and a Sec63 domain [16], [21], [22].…”

Section: Discussionmentioning

confidence: 99%

“…It is known that the first two adRP-assiociated mutations of hBrr2, p.S1087L and p.R1090L, are located at the α5 of the helical bundle in N-terminal of the first sec63 domain [16] involved in nucleic acid unwinding. Previous studies had elucidated that residues in Hel308, equivalent to hBrr2 residues S1087 and R1090, have direct contact with nucleic acids from Sec63 domain and are essential for duplex unwinding [16], [17], [22].…”

Section: Discussionmentioning

confidence: 99%

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A Novel Missense SNRNP200 Mutation Associated with Autosomal Dominant Retinitis Pigmentosa in a Chinese Family

et al. 2012

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The SNRNP200 gene encodes hBrr2, a helicase essential for pre-mRNA splicing. Six mutations in SNRNP200 have recently been discovered to be associated with autosomal dominant retinitis pigmentosa (adRP). In this work, we analyzed a Chinese family with adRP and identified a novel missense mutation in SNRNP200. To identify the genetic defect in this family, exome of the proband was captured and sequencing analysis was performed to exclude known genetic defects and find possible pathogenic mutations. Subsequently, candidate mutations were validated in affected family members using Sanger sequencing. A novel missense mutation, c.2653C>G transition (p.Q885E), in exon 20 of SNRNP200 was identified. The mutation co-segregated with the disease phenotype over four generations and was absent in 100 normal unaffected individuals. This mutation occurs at highly conserved position in hBrr2 and is predicted to have a functional impact, suggesting that hBrr2-dependent small nuclear riboproteins (snRNPs) unwinding and spliceosome activation is important in the pathogenesis of some variants of RP.

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Section: Resultsmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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A Novel Missense SNRNP200 Mutation Associated with Autosomal Dominant Retinitis Pigmentosa in a Chinese Family

et al. 2012

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“…4) ( g ) Domain organization in RecG-like protein is largely conserved, but PriA has a non-typical Zn finger inserted in the helicase domain 2 [66] (TRG – translocation by RecG) ( h ) Domain organization of Hel 308 [52]. The organization of the C-terminal domains is conserved in Brr2 [95,96]. (WH – winged helix, H1 – helical 1, H2 – helical 2, FN3 – fibronectin 3) ( i ) DEAH/RHA proteins have varying N-terminal domains, but show a very high degree of conservation in their C-termini, especially among the spliceosomal DEAH proteins.…”

Section: Figures and Tablementioning

confidence: 99%

“…Shown is the domain organization of Prp43 [53]. The domain organization of the C-terminus, with the exception of the OB-fold domain, resembles that of Ski2-like proteins [52,95,96]. (WH* - degenerated winged helix, Ratchet corresponds to H1 and H1 in the Ski2-like proteins) ( k ) NS3/NPH-II proteins have pronounced C- and N-terminal domains, but with the exception of the shown helical C-terminus of NS3 proteins from flaviviridae [51], no further information about these domains is available.…”

Section: Figures and Tablementioning

confidence: 99%

SF1 and SF2 helicases: family matters

Fairman-Williams

Guenther

Jankowsky

2010

Current Opinion in Structural Biology

789

945

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Helicases of the superfamily (SF) 1 and 2 are involved in virtually all aspects of RNA and DNA metabolism. SF1 and SF2 helicases share a catalytic core with high structural similarity, but different enzymes even within each superfamily perform a wide spectrum of distinct functions on diverse substrates. To rationalize similarities and differences between these helicases, we outline a classification based on protein families that are characterized by typical sequence, structural and mechanistic features. This classification complements and extends existing SF1 and SF2 helicase categorizations and highlights major structural and functional themes for these proteins. We discuss recent data in the context of this unifying view of SF1 and SF2 helicases.

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Retinitis Pigmentosa Mutations ofSNRNP200Enhance Cryptic Splice-Site Recognition

2013

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Mutations in SNRP200 gene cause autosomal-dominant retinal disorder retinitis pigmentosa (RP). The protein product of SNRNP200 is BRR2, a DExD/H box RNA helicase crucial for pre-mRNA splicing. In this study, we prepared p.S1087L and p.R1090L mutations of human BRR2 using bacterial artificial chromosome recombineering and stably expressed them in human cell culture. Mutations in BRR2 did not compromise snRNP assembly and both mutants were incorporated into the spliceosome just as the wild-type (wt) protein. Surprisingly, cells expressing RP mutants exhibited increased splicing efficiency of the LDHA gene. Next, we found that depletion of endogenous BRR2 enhanced usage of a β-globin cryptic splice site while splicing at the correct splice site was inhibited. Proper splicing of optimal and cryptic splice sites was restored in cells expressing BRR2-wt but not in cells expressing RP mutants. Taken together, our data suggest that BRR2 is an important factor in 5'-splice-site recognition and that the RP-linked mutations c.3260C>T (p.S1087L) and c.3269G>T (p.R1090L) affect this BRR2 function.

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Common Design Principles in the Spliceosomal RNA Helicase Brr2 and in the Hel308 DNA Helicase

Cited by 18 publications

References 0 publications

A Novel Missense SNRNP200 Mutation Associated with Autosomal Dominant Retinitis Pigmentosa in a Chinese Family

A Novel Missense SNRNP200 Mutation Associated with Autosomal Dominant Retinitis Pigmentosa in a Chinese Family

SF1 and SF2 helicases: family matters

Retinitis Pigmentosa Mutations ofSNRNP200Enhance Cryptic Splice-Site Recognition

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