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==Sex-Lethal Protein==
<StructureSection load='1b7f' size='350' side='right' caption='Sex-Lethal protein' scene=''>
<StructureSection load='1b7f' size='350' side='right' caption='Sex-Lethal protein' scene=''>
== Background ==
== Background ==
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'''Sex Lethal Protein''' (Sxl) is a splicing repressor in the male developmental pathway of [http://en.wikipedia.org/wiki/Sex-determination_system sex determination] of the common fruit fly, ''[http://en.wikipedia.org/wiki/Drosophila_melanogaster Drosophila melanogaster]''<ref name="Handa">PMID: 10217141</ref>. <scene name='78/783145/Sxl/1'>Sxl</scene> regulates [http://en.wikipedia.org/wiki/Alternative_splicing alternative splicing] pathways to promote the expression of female sex-linked proteins. In eukaryotes, splicing is carried out via the [http://en.wikipedia.org/wiki/Spliceosome spliceosome], a [http://en.wikipedia.org/wiki/Ribozyme ribozyme] -protein complex which binds to the 5’ and 3’ splice sites. As Sxl is a splicing repressor, it prevents the binding of the [http://en.wikipedia.org/wiki/U2AF2 U2AF] and [http://en.wikipedia.org/wiki/U1_spliceosomal_RNA U1 subunits] of the spliceosome at their respective splice sites, which represses the alternative splicing mechanism<ref name="Penalva">PMID: 12966139</ref>. As a result, the fruit fly expressing Sxl will produce mRNA transcripts encoding proteins for the female developmental pathway<ref name="Handa"/>.
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'''Sex Lethal Protein''' (Sxl) is a splicing repressor in the male developmental pathway of [http://en.wikipedia.org/wiki/Sex-determination_system sex determination] of the common fruit fly, ''[http://en.wikipedia.org/wiki/Drosophila_melanogaster Drosophila melanogaster]''<ref name="Handa">PMID: 10217141</ref>. <scene name='78/783145/Sxl/1'>Sxl</scene> regulates [http://en.wikipedia.org/wiki/Alternative_splicing alternative splicing] pathways to promote the expression of female sex-linked proteins. In eukaryotes, splicing is carried out via the [https://en.wikipedia.org/wiki/Spliceosome spliceosome], a [http://en.wikipedia.org/wiki/Ribozyme ribozyme]-protein complex which binds to the 5’ and 3’ splice sites. As Sxl is a splicing repressor, it prevents the binding of the [http://en.wikipedia.org/wiki/U2AF2 U2AF] and [http://en.wikipedia.org/wiki/U1_spliceosomal_RNA U1 subunits] of the spliceosome at their respective splice sites, which represses the alternative splicing mechanism<ref name="Penalva">PMID: 12966139</ref>. As a result, the fruit fly expressing Sxl will produce mRNA transcripts encoding proteins for the female developmental pathway<ref name="Handa"/>.
== Significance ==
== Significance ==
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[[Image:Sex Lethal Protein Structural Overview with Labels.png|300px|left|thumb| '''Figure 1.''' Structural overview of Sxl. RNA ligand colored in green is recognized and bound, while RNA ligand colored in grey is not bound. Image created in PyMol. Structure shown is [https://www.rcsb.org/structure/1b7f PDB:1b7f].]]
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[[Image:Sex Lethal Protein Structural Overview with Labels.png|300px|right|thumb| '''Figure 1.''' Structural overview of Sxl. RNA ligand colored in green is recognized and bound, while RNA ligand colored in grey is not bound. Image created in PyMol. Structure shown is [https://www.rcsb.org/structure/1b7f PDB:1b7f].]]
The Sxl RNA splicing targets encode for the transformer (''tra'') and the male-sex lethal (''msl-2'') proteins. ''Tra'' is a splicing activator for the female developmental pathway, and ''msl-2'' modulates [http://en.wikipedia.org/wiki/X_chromosome X chromosome] application in male fruit flies. The mechanism for how Sxl targets these pathways differs slightly. In both mechanisms, Sxl occupies the 3' splice site and prevents [http://en.wikipedia.org/wiki/U2AF2 U2AF] from binding. This causes the U2AF splicing factor to bind at a downstream splice site encoding proteins in the female developmental pathway. In ''msl-2'' targeting, Sxl also blocks the binding of another regulatory splicing factor, Rox8, and the [http://en.wikipedia.org/wiki/SnRNP U1 snRNP] at the 5’ splice site<ref name="Penalva"/>. Sxl can also control its own splicing pattern to conserve female expression. It does so by binding to [http://en.wikipedia.org/wiki/Exon Exon] 3 of its own RNA and creating an RNP complex to eliminate this exon. After removal of Exon 3, Sxl becomes active and female expression is maintained.
The Sxl RNA splicing targets encode for the transformer (''tra'') and the male-sex lethal (''msl-2'') proteins. ''Tra'' is a splicing activator for the female developmental pathway, and ''msl-2'' modulates [http://en.wikipedia.org/wiki/X_chromosome X chromosome] application in male fruit flies. The mechanism for how Sxl targets these pathways differs slightly. In both mechanisms, Sxl occupies the 3' splice site and prevents [http://en.wikipedia.org/wiki/U2AF2 U2AF] from binding. This causes the U2AF splicing factor to bind at a downstream splice site encoding proteins in the female developmental pathway. In ''msl-2'' targeting, Sxl also blocks the binding of another regulatory splicing factor, Rox8, and the [http://en.wikipedia.org/wiki/SnRNP U1 snRNP] at the 5’ splice site<ref name="Penalva"/>. Sxl can also control its own splicing pattern to conserve female expression. It does so by binding to [http://en.wikipedia.org/wiki/Exon Exon] 3 of its own RNA and creating an RNP complex to eliminate this exon. After removal of Exon 3, Sxl becomes active and female expression is maintained.
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=== ''Msl-2'' ===
=== ''Msl-2'' ===
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The alternative splicing of ''msl-2'' is reliant on Sxl binding to both the 5' and 3' splice sites (Fig. 3). Sxl binds at the 3' splice site, replacing U2AF as in ''tra'' splicing. Sxl also competes with [http://www.uniprot.org/uniprot/Q26281 Rox8], which binds to the first intron. As a result, Sxl prevents splicing of the first intron of the ''msl-2'' primary transcript. Sxl also binds to the poly- U sequences of the 3' UTR to repress translation (Fig.3)<ref name="Panalva">doi:10.1128/mmbr.67.3.343-359.2003</ref>. When Sxl targets ''msl-2'', the first intron is retained<ref name="Black"/>. However, the retained intron is in the [https://en.wikipedia.org/wiki/Untranslated_region 5' UTR] and does not affect the reading frame<ref name="Black"/>.
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The alternative splicing of ''msl-2'' is reliant on Sxl binding to both the 5' and 3' splice sites (Fig. 3). Sxl binds at the 3' splice site, replacing U2AF as in ''tra'' splicing. Sxl also competes with [http://www.uniprot.org/uniprot/Q26281 Rox8], which binds to the first intron. As a result, Sxl prevents splicing of the first intron of the ''msl-2'' primary transcript. Sxl also binds to the poly- U sequences of the 3' UTR to repress translation (Fig.3)<ref name="Panalva"/>doi:10.1128/mmbr.67.3.343-359.2003</ref>. When Sxl targets ''msl-2'', the first intron is retained<ref name="Black"/>. However, the retained intron is in the [https://en.wikipedia.org/wiki/Untranslated_region 5' UTR] and does not affect the reading frame<ref name="Black"/>.
=== Structural Basis for Recognition of Poly-U Sequences ===
=== Structural Basis for Recognition of Poly-U Sequences ===

Revision as of 18:14, 30 March 2018

Contents

Sex-Lethal Protein

Sex-Lethal protein

Drag the structure with the mouse to rotate

Additional Reading

For more information on the U2AF splicing factor.


Relevance

As Sxl functions as a splicing repressor, it may give insight into the effects of varying mechanisms of alternate splicing both in flies and other species. Sxl may also lead to understanding of human alternative splicing factors. As an RNA binding protein, research regarding Sxl may contribute to the understanding of enzymes with RNA recognition motifs. The Sxl RNP motif of RBD1 is also conserved in the ELAV family of proteins[1].

References

  1. 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 1.19 1.20 1.21 1.22 1.23 Handa N, Nureki O, Kurimoto K, Kim I, Sakamoto H, Shimura Y, Muto Y, Yokoyama S. Structural basis for recognition of the tra mRNA precursor by the Sex-lethal protein. Nature. 1999 Apr 15;398(6728):579-85. PMID:10217141 doi:10.1038/19242
  2. 2.0 2.1 Penalva LO, Sanchez L. RNA binding protein sex-lethal (Sxl) and control of Drosophila sex determination and dosage compensation. Microbiol Mol Biol Rev. 2003 Sep;67(3):343-59, table of contents. PMID:12966139
  3. 3.0 3.1 3.2 3.3 3.4 Black DL. Mechanisms of alternative pre-messenger RNA splicing. Annu Rev Biochem. 2003;72:291-336. doi: 10.1146/annurev.biochem.72.121801.161720., Epub 2003 Feb 27. PMID:12626338 doi:http://dx.doi.org/10.1146/annurev.biochem.72.121801.161720

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