User:Jeremy C. Caylor/Sandbox 1
From Proteopedia
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=Sex Lethal= | =Sex Lethal= | ||
| - | <StructureSection load='1B7F' size='350' side='right' caption='Sex lethal (PDB: 1B7F)' scene='78/782600/Opening_image/1'> | ||
== Introduction == | == Introduction == | ||
Sex lethal (Sxl) is an RNA-binding protein that plays a vital role in sex determination and dosage compensation in ''Drosophila melanogaster'', the common fruit fly <ref name="Black">doi: 10.1146/annurev.biochem.72.121801.161720</ref>. Sxl binds specifically to the continuous single-stranded RNA sequence 5’-UGUUUUUUU <ref name="Handa">doi:10.1038/19242 | Sex lethal (Sxl) is an RNA-binding protein that plays a vital role in sex determination and dosage compensation in ''Drosophila melanogaster'', the common fruit fly <ref name="Black">doi: 10.1146/annurev.biochem.72.121801.161720</ref>. Sxl binds specifically to the continuous single-stranded RNA sequence 5’-UGUUUUUUU <ref name="Handa">doi:10.1038/19242 | ||
</ref>. Functional copies of Sxl are expressed only in female fruit flies, where they induce sex-specific splicing patterns in the transcript of the Transformer (Tra) gene that lead to its function. Tra initiates a cascade that results in the development of female structures and behaviors. Sxl binds to its recognition element in the Tra pre-mRNA transcript, thereby blocking association of the splicing factor U2AF at the nearby splice site. Without the association of this essential splicing factor, the 3’ splice site shifts downstream, causing the removal of a premature stop codon and preventing truncation and inactivation of the Tra protein <ref name="Black" />. The pre-mRNA transcript of Male-specific lethal 2 (Msl2) is the downstream target through which Sxl regulates dosage compensation. Active Sxl protein (in females) binds to two recognition elements on Msl2 causing the retention of the first intron in the 5’UTR of Msl2. Sxl bound at this intron then blocks translation, preventing expression of Msl2 in females <ref name="Black" />. Without Msl2 protein, the Male specific lethal complex cannot form and carry out its function of upregulating expression of genes on the X chromosome <ref name="dosage">Georgiev P, Chlamydas S, Akhtar A. Drosophila dosage compensation. Fly 2011; 5(2):147-154. https://doi.org/10.4161/fly.5.2.14934</ref>. | </ref>. Functional copies of Sxl are expressed only in female fruit flies, where they induce sex-specific splicing patterns in the transcript of the Transformer (Tra) gene that lead to its function. Tra initiates a cascade that results in the development of female structures and behaviors. Sxl binds to its recognition element in the Tra pre-mRNA transcript, thereby blocking association of the splicing factor U2AF at the nearby splice site. Without the association of this essential splicing factor, the 3’ splice site shifts downstream, causing the removal of a premature stop codon and preventing truncation and inactivation of the Tra protein <ref name="Black" />. The pre-mRNA transcript of Male-specific lethal 2 (Msl2) is the downstream target through which Sxl regulates dosage compensation. Active Sxl protein (in females) binds to two recognition elements on Msl2 causing the retention of the first intron in the 5’UTR of Msl2. Sxl bound at this intron then blocks translation, preventing expression of Msl2 in females <ref name="Black" />. Without Msl2 protein, the Male specific lethal complex cannot form and carry out its function of upregulating expression of genes on the X chromosome <ref name="dosage">Georgiev P, Chlamydas S, Akhtar A. Drosophila dosage compensation. Fly 2011; 5(2):147-154. https://doi.org/10.4161/fly.5.2.14934</ref>. | ||
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| + | <StructureSection load='1B7F' size='350' side='right' caption='Sex lethal (PDB: 1B7F)' scene='78/782600/Opening_image/1'> | ||
== Structure == | == Structure == | ||
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1. Hydrogen binding to the RNA backbone: | 1. Hydrogen binding to the RNA backbone: | ||
There is an unusual abundance of interactions between the protein and the RNA backbone of the ligand. RRM2 creates four hydrogen bonds with U3 and G4 backbones at Y214, N241, R252, and R258. RRM1 creates two hydrogen bonds with the U9 backbone at N130, R155. | There is an unusual abundance of interactions between the protein and the RNA backbone of the ligand. RRM2 creates four hydrogen bonds with U3 and G4 backbones at Y214, N241, R252, and R258. RRM1 creates two hydrogen bonds with the U9 backbone at N130, R155. | ||
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2. Hydrogen binding to the bases: | 2. Hydrogen binding to the bases: | ||
There are numerous hydrogen bonds between the residues and the nucleotide bases. RRM2 creates five hydrogen bonds with U3-G4-U5 at the main chains of N217, R252, and A289 and the side chains of N212 and Q239. RRM1 creates nine hydrogen bonds between U6-U7-U8-U9-U10-U11 at the main chains ofS165, R195, R202, G204 and the side chains of N126, Q134, R155, K197 and R202. | There are numerous hydrogen bonds between the residues and the nucleotide bases. RRM2 creates five hydrogen bonds with U3-G4-U5 at the main chains of N217, R252, and A289 and the side chains of N212 and Q239. RRM1 creates nine hydrogen bonds between U6-U7-U8-U9-U10-U11 at the main chains ofS165, R195, R202, G204 and the side chains of N126, Q134, R155, K197 and R202. | ||
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3. Intermolecular stacking: | 3. Intermolecular stacking: | ||
Intermolecular stacking between the aromatic side chains and the nucleotide bases also contributes to RNA binding. In RRM2, U3-G4-U5 stack with V254, Y214, and F256 respectively. In RRM1, U6 stacks with Y131 and R195, U9 stacks with N130, and U11 stacks with F170. | Intermolecular stacking between the aromatic side chains and the nucleotide bases also contributes to RNA binding. In RRM2, U3-G4-U5 stack with V254, Y214, and F256 respectively. In RRM1, U6 stacks with Y131 and R195, U9 stacks with N130, and U11 stacks with F170. | ||
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<scene name='78/782600/Rrm1_res_h-bond_w_bases/1'>RRM1 residues hydrogen bonding to ligand nucleotide bases</scene> | <scene name='78/782600/Rrm1_res_h-bond_w_bases/1'>RRM1 residues hydrogen bonding to ligand nucleotide bases</scene> | ||
| - | == Mutation == | ||
</StructureSection> | </StructureSection> | ||
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| + | == Mutation == | ||
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== References == | == References == | ||
<references/> | <references/> | ||
Revision as of 13:34, 28 March 2018
Contents |
Sex Lethal
Introduction
Sex lethal (Sxl) is an RNA-binding protein that plays a vital role in sex determination and dosage compensation in Drosophila melanogaster, the common fruit fly [1]. Sxl binds specifically to the continuous single-stranded RNA sequence 5’-UGUUUUUUU [2]. Functional copies of Sxl are expressed only in female fruit flies, where they induce sex-specific splicing patterns in the transcript of the Transformer (Tra) gene that lead to its function. Tra initiates a cascade that results in the development of female structures and behaviors. Sxl binds to its recognition element in the Tra pre-mRNA transcript, thereby blocking association of the splicing factor U2AF at the nearby splice site. Without the association of this essential splicing factor, the 3’ splice site shifts downstream, causing the removal of a premature stop codon and preventing truncation and inactivation of the Tra protein [1]. The pre-mRNA transcript of Male-specific lethal 2 (Msl2) is the downstream target through which Sxl regulates dosage compensation. Active Sxl protein (in females) binds to two recognition elements on Msl2 causing the retention of the first intron in the 5’UTR of Msl2. Sxl bound at this intron then blocks translation, preventing expression of Msl2 in females [1]. Without Msl2 protein, the Male specific lethal complex cannot form and carry out its function of upregulating expression of genes on the X chromosome [3].
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Mutation
References
- ↑ 1.0 1.1 1.2 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
- ↑ 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
- ↑ Georgiev P, Chlamydas S, Akhtar A. Drosophila dosage compensation. Fly 2011; 5(2):147-154. https://doi.org/10.4161/fly.5.2.14934
