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Literature summary for 3.6.4.13 extracted from
- Functions and regulation of the Brr2 RNA helicase during splicing (2016), Cell Cycle, 15, 3362-3377 .
Cloned(Commentary)
| Cloned (Comment) | Organism |
|---|---|
| gene BRR2 | Saccharomyces cerevisiae |
| gene SNRNP200 | Homo sapiens |
Protein Variants
| Protein Variants | Comment | Organism |
|---|---|---|
| E909K | site-directed mutagenesis, the temperature-sensitive mutant, encoded by the slt22-1 allele, is synthetically lethal with mutations in U2 or U6 snRNAs that affect the stability or conformation of U2/U6 helix II. The ATPase activity of this variant is no longer stimulated by a U2/ U6 duplex, it is proposed that Brr2 might proofread U2/U6 interactions. The E909K exchange in Brr2 blocks splicing in extracts at or before the first catalytic step and leads to the appearance of an off-pathway spliceosomal particle following B complex formation, which lacks U4 and U5 snRNAs | Saccharomyces cerevisiae |
| G858R | site-directed mutagenesis, the mutant shows differing cross-linking profiles compared to wild-type Brr2, the mutation is in the NC 5'HP/separator loop with U6 snRNA | Saccharomyces cerevisiae |
| R681C | site-directed mutagenesis, a brr2 mutation linked to the RP33 form of autosomal dominant retinitis pigmentosa, it maps to the linker between the RecA domains of the NC, the mutation leads to altered Brr2 ATPase activity and aberrant partitioning of spliceosomes along activation and discard pathways | Saccharomyces cerevisiae |
| R681H | site-directed mutagenesis, a brr2 mutation linked to the RP33 form of autosomal dominant retinitis pigmentosa, it maps to the linker between the RecA domains of the NC, the mutation leads to altered Brr2 ATPase activity and aberrant partitioning of spliceosomes along activation and discard pathways | Saccharomyces cerevisiae |
| V683L | site-directed mutagenesis, a brr2 mutation linked to the RP33 form of autosomal dominant retinitis pigmentosa, it maps to the linker between the RecA domains of the NC, the mutation leads to altered Brr2 ATPase activity and aberrant partitioning of spliceosomes along activation and discard pathways | Saccharomyces cerevisiae |
| Y689C | site-directed mutagenesis, a brr2 mutation linked to the RP33 form of autosomal dominant retinitis pigmentosa, it maps to the beginning of the RecA2 domain | Saccharomyces cerevisiae |
Localization
| Localization | Comment | Organism | GeneOntology No. | Textmining |
|---|---|---|---|---|
| nucleus | - |
Homo sapiens | 5634 | - |
| nucleus | - |
Saccharomyces cerevisiae | 5634 | - |
Metals/Ions
| Metals/Ions | Comment | Organism | Structure |
|---|---|---|---|
| Mg2+ | required | Homo sapiens |  |
| Mg2+ | required | Saccharomyces cerevisiae | |
Natural Substrates/ Products (Substrates)
| Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| ATP + H2O | Homo sapiens | - |
ADP + phosphate | - |
? | |
| ATP + H2O | Saccharomyces cerevisiae | - |
ADP + phosphate | - |
? | |
| ATP + H2O | Saccharomyces cerevisiae ATCC 204508 | - |
ADP + phosphate | - |
? | |
Organism
| Organism | UniProt | Comment | Textmining |
|---|---|---|---|
| Homo sapiens | O75643 | - |
- |
| Saccharomyces cerevisiae | P32639 | - |
- |
| Saccharomyces cerevisiae ATCC 204508 | P32639 | - |
- |
Substrates and Products (Substrate)
| Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| ATP + H2O | - |
Homo sapiens | ADP + phosphate | - |
? | |
| ATP + H2O | - |
Saccharomyces cerevisiae | ADP + phosphate | - |
? | |
| ATP + H2O | - |
Saccharomyces cerevisiae ATCC 204508 | ADP + phosphate | - |
? | |
| additional information | Brr2 participates in a transient opening of the catalytic core between the 2 steps of splicing, which is characterized by the intermittent disruption of U6-5SS and U2-U6 interactions | Homo sapiens | ? | - |
- |
|
| additional information | Brr2 participates in a transient opening of the catalytic core between the 2 steps of splicing, which is characterized by the intermittent disruption of U6-5SS and U2-U6 interactions | Saccharomyces cerevisiae | ? | - |
- |
|
| additional information | Brr2 participates in a transient opening of the catalytic core between the 2 steps of splicing, which is characterized by the intermittent disruption of U6-5SS and U2-U6 interactions | Saccharomyces cerevisiae ATCC 204508 | ? | - |
- |
|
Synonyms
| Synonyms | Comment | Organism |
|---|---|---|
| BRR2 | - |
Saccharomyces cerevisiae |
| Brr2 RNA helicase | - |
Homo sapiens |
| Brr2 RNA helicase | - |
Saccharomyces cerevisiae |
| Ski2-like helicase | - |
Homo sapiens |
| Ski2-like helicase | - |
Saccharomyces cerevisiae |
| SNRNP200 | - |
Homo sapiens |
| spliceosomal RNA helicase | - |
Homo sapiens |
| spliceosomal RNA helicase | - |
Saccharomyces cerevisiae |
General Information
| General Information | Comment | Organism |
|---|---|---|
| evolution | SF2 helicases can be grouped into 5 families, 3 of which are represented among the spliceosomal remodeling enzymes: 3 DEAD box proteins (Prp5, Sup2/UAP56, Prp28) act during initial spliceosome assembly and activation, a single Ski2-like helicase (Brr2) is involved in spliceosome activation and 4 DEAH/RHA enzymes (Prp2, Prp16, Prp22, Prp43) are required during spliceosome activation, catalysis and disassembly | Homo sapiens |
| evolution | SF2 helicases can be grouped into 5 families, 3 of which are represented among the spliceosomal remodeling enzymes: 3 DEAD box proteins (Prp5, Sup2/UAP56, Prp28) act during initial spliceosome assembly and activation, a single Ski2-like helicase (Brr2) is involved in spliceosome activation and 4 DEAH/RHA enzymes (Prp2, Prp16, Prp22, Prp43) are required during spliceosome activation, catalysis and disassembly | Saccharomyces cerevisiae |
| metabolism | the enzyme is involved in the pre-mRNA splicing cycle by the spliceosome, reaction steps in processing, detailed overview. The most dramatic rearrangements occur during spliceosome activation, where the Prp28 helicase aids in the displacement of U1 snRNA from the 5SS,8,23,24 followed by Brr2 unwinding the U4 and U6 snRNAs and leading to displacement of U4 snRNA and U4/U6-bound proteins. Brr2 requires tight regulation | Homo sapiens |
| metabolism | the enzyme is involved in the pre-mRNA splicing cycle by the spliceosome, reaction steps in processing, detailed overview. The most dramatic rearrangements occur during spliceosome activation, where the Prp28 helicase aids in the displacement of U1 snRNA from the 5SS,8,23,24 followed by Brr2 unwinding the U4 and U6 snRNAs and leading to displacement of U4 snRNA and U4/U6-bound proteins. Brr2 requires tight regulation | Saccharomyces cerevisiae |
| additional information | the structure of Brr2 differs decisively from that of other spliceosomal helicases, enzyme structure analysis, detailed overview. Comparison of human and yeast enzymes, comparative modeling | Homo sapiens |
| additional information | the structure of Brr2 differs decisively from that of other spliceosomal helicases, enzyme structure analysis, detailed overview. Comparison of human and yeast enzymes, comparative modeling. Analysis of the mechanism of spliceosome activation using multi-wavelength single-molecule co-localization spectroscopy demonstrates that after tri-snRNP binding, the spliceosome can either proceed to activation or release U4 and U5 snRNAs. The ATP-dependent loss of U4 and U5 snRNAs is suggested to represent Prp28-mediated displacement of the tri-snRNP | Saccharomyces cerevisiae |
| physiological function | functions and regulation of the Brr2 RNA helicase during splicing, structure-function analysis, overview. Brr2 is transported to the nucleus independent of other U5 snRNP components and its helicase activity may have to be shut off during this phase to avoid detrimental off-target effects. Once assembled in the nucleus, mature U5 snRNP joins the U4/U6 di-snRNP to form the U4/U6-U5 trisnRNP, in which Brr2 already encounters its U4/U6 di-snRNA substrate before incorporation into the spliceosome. Brr2 requires tight regulation. Isolated Brr2 is a comparatively weak helicase and its U4/U6 di-snRNA substrate is stabilized by extensive base pairing and bound proteins, suggesting that the helicase may also depend on specific activation to efficiently unwind the U4/U6 duplex at the right time. Implications for Brr2-dependent proofreading and regulation of alternative splicing, model for putative Brr2-mediated enhancement of splicing fidelity and regulation of alternative splicing. Brr2 may be more or less prone to disrupt the tri-snRNP in a non-productive fashion, thus differentially channeling the different substrates along the splicing or discard pathways. Similarly, depending on the level of Brr2 inhibition in competing alternative splicing scenarios, the helicase may elicit spliceosome activation slowly or quickly, kinetically controlling the levels of protein isoforms produced | Homo sapiens |
| physiological function | functions and regulation of the Brr2 RNA helicase during splicing, structure-function analysis, overview. Brr2 is transported to the nucleus independent of other U5 snRNP components and its helicase activity may have to be shut off during this phase to avoid detrimental off-target effects. Once assembled in the nucleus, mature U5 snRNP joins the U4/U6 di-snRNP to form the U4/U6-U5 trisnRNP, in which Brr2 already encounters its U4/U6 di-snRNA substrate before incorporation into the spliceosome. Brr2 requires tight regulation. Isolated Brr2 is a comparatively weak helicase and its U4/U6 di-snRNA substrate is stabilized by extensive base pairing and bound proteins, suggesting that the helicase may also depend on specific activation to efficiently unwind the U4/U6 duplex at the right time. Implications for Brr2-dependent proofreading and regulation of alternative splicing, model for putative Brr2-mediated enhancement of splicing fidelity and regulation of alternative splicing. Brr2 may be more or less prone to disrupt the tri-snRNP in a non-productive fashion, thus differentially channeling the different substrates along the splicing or discard pathways. Similarly, depending on the level of Brr2 inhibition in competing alternative splicing scenarios, the helicase may elicit spliceosome activation slowly or quickly, kinetically controlling the levels of protein isoforms produced | Saccharomyces cerevisiae |
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