User:Kyle Burton/Sandbox1
From Proteopedia
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<scene name='78/783145/R155_intxn_with_u11/3'>R155 interaction with U11</scene> | <scene name='78/783145/R155_intxn_with_u11/3'>R155 interaction with U11</scene> | ||
| - | <scene name='78/783145/Aromatic_stacking/ | + | <scene name='78/783145/Aromatic_stacking/3'>Aromatic stacking between G4/Tyr-214 and U5/Phe-256</scene> |
<scene name='78/783145/U8_with_s165_and_y166/1'>U8 interaction with Ser-165 and Tyr-166</scene> | <scene name='78/783145/U8_with_s165_and_y166/1'>U8 interaction with Ser-165 and Tyr-166</scene> | ||
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<scene name='78/783145/U5_u6_u7_loop/2'>U5-U7 Loop</scene> | <scene name='78/783145/U5_u6_u7_loop/2'>U5-U7 Loop</scene> | ||
| + | <scene name='78/783145/U7_u8_stacking/1'>U7-U8 Stacking</scene> | ||
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| + | <scene name='78/783145/U9_with_interdomain_linker/1'>U9 with Interdomain Linker</scene> | ||
| + | |||
| + | <scene name='78/783145/Molecule_base_origin/4'>TextToBeDisplayed</scene> | ||
Revision as of 23:26, 28 March 2018
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This is a default text for your page Kyle Burton/Sandbox1. Click above on edit this page to modify. Be careful with the < and > signs. You may include any references to papers as in: the use of JSmol in Proteopedia [1] or to the article describing Jmol [2] to the rescue.
Contents |
Background
Sex Lethal Protein (Sxl) is a splicing repressor in the male developmental pathway of sex determination of the common fruit fly, Drosophila melanogaster. Sxl regulates alternative splicing pathways to promote the expression of female sex-linked proteins. In eukaryotes, splicing is carried out via the spliceosome, a ribozyme-protein complex which binds to the 5’ and 3’ splice sites. As Sxl is a splicing repressor, it prevents the binding of the U2AF and U1 subunits of the spliceosome at their respective splice sites, which represses the alternative splicing mechanism. As a result, the fruit fly expressing Sxl will produce mRNA transcripts encoding proteins for the female developmental pathway.
Significance
The Sxl RNA splicing targets encode for the transformer (Tra) and the male-sex lethal (Msl-2) proteins. Tra is a splicing activator in the female developmental pathway, and Msl-2 modulates 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 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, TIA-1, and the U1 snRNP at the 5’ splice site. Sxl can also control its own splicing pattern to conserve female expression. It does so by binding to 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.
Structure
Sxl is composed of two asymmetric RNA binding domains (RBD1 and RBD2) which recognize a poly-uridine site in the pre-mRNA transcript. Each RBD is comprised of two alpha helices and one antiparallel four-stranded β sheet. The β sheets face each other, lining the electropositive V-shaped cleft. The inter-domain linker forms a distorted 310 helix which helps to form the V-shaped cleft into which the pre-mRNA sequence binds. Sxl binds to UGUUUUUUU sequence of GUUGUUUUUUUU in tra. RBD1 binds U6-U11 and RBD2 binds U3, G4, and U5. Although the two RBDs do not interact with each other, this nine-ribonucleotide sequence must be recognized continuously to prevent U2AF from binding at the 3’ splice site. The binding of Sxl to the pre-mRNA occurs in an electropositive pocket due to extensive interactions with the RNA phosphate backbone and negatively charged residues. Since Sxl binds primarily with the phosphate backbone, the protein residues are not highly conserved.
The ligand pre-mRNA sequence forms a characteristic loop at U5, U6, and U7. This interaction is stabilized by pi stacking between the G4 and U5 nucleotides and residues Tyr 214 and Phe 256. The nucleobases are exposed to residues on Sxl due to the 2’ endo conformation of all the nucleotides except for U8, which maintains a 3’ endo conformation. U2AF is a more general splicing factor than Sxl, preferring cytidine-containing poly-uridine pre-mRNA sequences, so Sxl binds to the guanosine-containing pre-mRNA with a 104-fold greater affinity.
The structural interactions with regards to the targeting of the 5' splice site and of its own mRNA transcript are much less understood than the competition of Sxl with U2AF at the 3' splice site.
Disease
Relevance
Structural highlights
This is a sample scene created with SAT to by Group, and another to make of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.
</StructureSection>
References
- ↑ Hanson, R. M., Prilusky, J., Renjian, Z., Nakane, T. and Sussman, J. L. (2013), JSmol and the Next-Generation Web-Based Representation of 3D Molecular Structure as Applied to Proteopedia. Isr. J. Chem., 53:207-216. doi:http://dx.doi.org/10.1002/ijch.201300024
- ↑ Herraez A. Biomolecules in the computer: Jmol to the rescue. Biochem Mol Biol Educ. 2006 Jul;34(4):255-61. doi: 10.1002/bmb.2006.494034042644. PMID:21638687 doi:10.1002/bmb.2006.494034042644
