User:Integrated science guy/Brr2

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Brr2


BACKGROUND


Brr2 belongs to a family termed DExD/H box proteins[1] and is required for catalytic activation and disassembly of the spliceosome[2]. The spliceosome is a highly dyn amic RNA protein machine that requiring the ordered binding and release of five small nuclear ribonuclear proteins(snRNPS)to the intron containing pre-Mrna[3]. It has been shown that Brr2 can separate U4 and U6 snRNPS from a RNP-complex consisting of U1,U2,U5 and U4/U6 snRNPS[4]; which is pivotal for the recycling of the spliceosome.

STRUCTURE

In is important to look at the association of U4/U6; which forms a phylogenetically highly conserved Y-shaped interaction domain, consisting of two intermolecular helices (stem1 and stem2)[5].This association enables us To better understand how Brr2 catalytically unwinds theRNA, thus dissociating U4/U6 resulting in free U4. We must examine the structural characteristics of this large spliceosomal protein (246KDa in yeast)[6]. It contains a N-terminal region, where it is predicted to lack tertiary structure and a tandem repeat of helical cassettes, where both cassettes contain dual Rec A domains and a portion that resembles the sec63p sub-unit of the ER[7]. And on the other end the C-terminal sec63 unit of Brr2 contains three domains[8]


MECHANISM/INTERACTIONS


By rational mutagenesis combined with U4/U6 di-snRNA unwinding assays it was shown how the Rec A domains and the sec 63 unit form a functional unit that is capable of unwinding RNA[9]. The C-terminal region of Prp 8 has been demonstrated to bind to Brr2 creating a complex that is capable of successful linkage to U4/U6[10]. It is believed that the motif in the first helicase domain is critical forATPase function, cell viability and U4/U6 unwinding[11], where the second helicase domain can be altered without consequence.

The proposed mechanism of Brr2 is brought about by its H2 and S2 domains that share similarities to the Hel308 modules along with its N-terminal domain[12]. The actual mechanics of the unwinding of the U4/U6 association requires disruption of base pairs via Brr2helicaseRNA andATP[13].


BIOLOGICAL ROLE


The Brr2 yeast protein is a key component of the U5 snRNP[14], and it has been shown to mediateATP dependent dissociation[15], when binding to form the complex termed the triple snurp (U4/U6 and U5). This tri-small nuclear ribonuclear protein is a highly conserved evolutionary spliceosome subunit[16]. In order to accomplish the unnealling of the U4/U6 snRNA duplex, the U5 along with its components namely, but not limited to Brr2 must bind to the pre-established complex [17]. In the cell the regeneration and dissociation of the snRNPS and proteins in the spliceosome are accomplished by an antagonistic association between prp24 and Brr2[18].


HOMOLOGS

It has been shown recently that a number of spliceosome proteins have been shown to be conserved from yeast to humans.[19]Brr2 is the yeast homolog of the hU5-200k.This was identified by the cold-sensitive mutant Brr2-1 which was shown in the experiment to be ineffective for pre-Mrna splcing[20].The U4/U6U5 tri-snRNP are unwound by the RNA helicase Brr2/U5-200k by the same mechanism [21]. Like Brr2 it has been shown that U5-200k has conserved domains, such as the DEAD/DEAH box helicases and Sec63 domains and displays a strong interaction with U5 snRNA[22]. 



[23]== References


  1. ^ Guthrie, Christine (December 2008). "ATP-dependent unwinding of U4/U6 snRNAs by the Brr2 helicase requires the C-terminus of Prp8". Nature Structural&Molecular Biology. 16: 42–48. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)CS1 maint: date and year (link)
  2. ^ Bujnicki (August 2009). "Common design principles in the Spliceosomal RNA helicase Brr2 and in the Hel 308 DNA Helicase". Molecular Cell. 35 (4): 454–466. doi:10.1016/j.molcel.2009.08.006. PMID 19716790. {{cite journal}}: Unknown parameter |fir st= ignored (help)CS1 maint: date and year (link)
  3. ^ Guthrie, Christine (December 2008). "ATP-dependent unwinding of U4/U6 snRNAs by the Brr2 helicase requires the C-terminus of Prp8". Nature Structural&Molecular Biology. 16: 42–48. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)CS1 maint: date and year (link)
  4. ^ Abelson, John N (1997). "Prp43:An RNA helicase-like factor involved in spliceosome assembly". Proc.Natl.Acad.Sci.USA. 94 (22): 11798–11802. doi:10.1073/pnas.94.22.11798. PMID 9342317. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  5. ^ Luhrmann, Rienhard (2002). "Hierachial clustered protein interactions with U4/U6 snRNA: a biochemical role for U4/U6 proteins". The EMBO. 21 (20): 5527–5538. doi:10.1093/emboj/cdf544. PMC 129076. PMID 12374753. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  6. ^ Bujnicki, Janusz M (August 2009). "Common design principles in the spliceosomal RNA helicase Brr2 and in the Hel308 DNA helicase". Molecular Cell. 35 (4): 454–466. doi:10.1016/j.molcel.2009.08.006. PMID 19716790.{{cite journal}}: CS1 maint: date and year (link)
  7. ^ Bujnicki, Janusz (August 2009). "Common design principles in the Spliceosome RNA helicase Brr2 and in the Hel308 DNA Helicase". Molecular Cell. 35 (4): 454–466. doi:10.1016/j.molcel.2009.08.006. PMID 19716790.{{cite journal}}: CS1 maint: date and year (link)
  8. ^ Guthrie, Christine (December 2008). "ATP-dependent unwinding of U4/U6 snRNAs by the Brr2 Helicase requires the C-terminus of Prp8". Nature Structural&Molecular Biology. 16: 42–48. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)CS1 maint: date and year (link)
  9. ^ Bujnicki, Janusz (August 2009). "Common design principles in the Spliceosomal RNA Helicase Brr2 and in the Hel308 DNA Helicase". Molecular Cell. 35 (4): 454–466. doi:10.1016/j.molcel.2009.08.006. PMID 19716790.{{cite journal}}: CS1 maint: date and year (link)
  10. ^ Guthrie, Christine (June 2009). "Structural evidence for consecutive Hel308-like modules in the Spliceosomal ATPase Brr2". Nature Structural&Molecular Biology. 16: 731–739.{{cite journal}}: CS1 maint: date and year (link)
  11. ^ Guthrie, Christine (june 2009). "Structural evidence for consecutive Hel308-like modules in the spliceosomal ATPase Brr2". Nature Structural&Molecular Biology. 16: 731–739. {{cite journal}}: Check date values in: |date= (help)CS1 maint: date and year (link)
  12. ^ Guthrie, Christine (june 2009). "Structural evidence for consecutive Hel308-like modules in the Spliceosomal ATPase Brr2". Nature Structural& Molecular Biology. 16 (7): 731–739. doi:10.1038/nsmb.1625. PMC 2743687. PMID 19525970. {{cite journal}}: Check date values in: |date= (help)CS1 maint: date and year (link)
  13. ^ Guthrie, Christine (july 1998). "RNA unwinding in U4/U6 snRNPs requires ATP hydrolosis and the DEIH-box splicing factor Brr2". Current Biology. 8 (15): 847–855. doi:10.1016/S0960-9822(07)00345-4. PMID 9705931. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)CS1 maint: date and year (link)
  14. ^ Bujnicki, Janusz N (August 2009). "Common design principles in the Spliceosomal RNA Helicase Brr2 and in the Hel308 DNA Helicase". Molecular Cell. 35 (4): 454–466. doi:10.1016/j.molcel.2009.08.006. PMID 19716790.{{cite journal}}: CS1 maint: date and year (link)
  15. ^ Luking, Angelika (1998). "The Protein Family of RNA Helicases". Critical Reviews in Biochem&Molecular Biology. 33 (4): 259–296. doi:10.1080/10409239891204233. PMID 9747670. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  16. ^ Berthold, Karagoz Eli (2008). "Localization of Prp8,Brr2,Snu114 and U4/U6 proteins in the yeast tri-snRNP by electron microscopy". Nature Structural&Molecular Biology. 15: 1206–1212.
  17. ^ Berthold, Karagoz Eli (2008). "Localization of Prp8,Brr2,Snu114 and U4/U6 proteins in the yeast tri-snRNP by electron microscopy". Nature Structural&Molecular Biology. 15: 1206–1212.
  18. ^ Guthrie, Christine (july 1998). "RNA unwinding in U4/U6 snRNPs requires ATP hydroloysis and the DEIH-box splicing factor Brr2". Current Biology. 8 (15): 847–855. doi:10.1016/S0960-9822(07)00345-4. PMID 9705931. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)CS1 maint: date and year (link)
  19. ^ Reed, Robin (1998). "Human Homologs of yeast Prp16 and Prp17 reveal conservation of the mechanism for catalytic step2 of pre-Mrna splicing". Of EMBO. 17 (7): 2095–2106. doi:10.1093/emboj/17.7.2095. PMC 1170554. PMID 9524131. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  20. ^ Lamond, Angus L (1998). "Spliceosome assembly: The unwinding role of DEAD-box proteins". Current Biology. 8 (15): R532–R534. doi:10.1016/S0960-9822(07)00340-5. PMID 9705927. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  21. ^ Bindereif, Albrecht (2008). "3'-Cyclic phosphorylation of U6 snRNA leads to recruitment of recycling factor of recycling factor p110 through Lsm proteins". Imaging in Development Biology. 14: 1532–1538.
  22. ^ Ambrosia, Daniela (March 2011). "New insights into trypanosomatid U5 small nuclear ribonucleoproteins". Mem.Inst Oswaldo Cruz,Rio de Janiero. 106 (2): 130–138. doi:10.1590/S0074-02762011000200003. PMID 21537670.{{cite journal}}: CS1 maint: date and year (link)
  23. ^ Cite error: The named reference undefined was invoked but never defined (see the help page).



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