User:Jeremy C. Caylor/Sandbox 1

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The RNA <scene name='78/782599/Ligand_only/2'>ligand</scene> bound by Sxl is 9 nucleotides long—UGUUUUUUU. This ligand lacks intramolecular base pairs—a characteristic that would typically assist in RNA recognition—and therefore presents with many unique features. Sxl fixes U3-U11 in a specific elongated conformation. <scene name='78/782599/U6-11/2'>U6-U11</scene> interact within the strongly electropositive v-shaped cleft, while <scene name='78/782600/U3-u5/5'>U3-G4-U5</scene> are bound to a positively charged surface on RRM2 <ref name="Handa" />. The kink in the middle of the ligand is created by hydrogen bonds between the 2’OH's of U5 and U6 and the phosphate group of U8, as well as between the 2’OH of U7 and the phosphate group of U5. This is kink is also facilitated by the only intramolecular stacking pair in the ligand, U7 and U8. All of the nucleotides besides U8 are in the C2’-endo conformation. This orientation allows the bases to be highly exposed to the protein and therefore increases specificity. The low number of intramolecular stacking regions and the large number of C2’-endo conformations deem this ligand unique<ref name="Handa" />.
The RNA <scene name='78/782599/Ligand_only/2'>ligand</scene> bound by Sxl is 9 nucleotides long—UGUUUUUUU. This ligand lacks intramolecular base pairs—a characteristic that would typically assist in RNA recognition—and therefore presents with many unique features. Sxl fixes U3-U11 in a specific elongated conformation. <scene name='78/782599/U6-11/2'>U6-U11</scene> interact within the strongly electropositive v-shaped cleft, while <scene name='78/782600/U3-u5/5'>U3-G4-U5</scene> are bound to a positively charged surface on RRM2 <ref name="Handa" />. The kink in the middle of the ligand is created by hydrogen bonds between the 2’OH's of U5 and U6 and the phosphate group of U8, as well as between the 2’OH of U7 and the phosphate group of U5. This is kink is also facilitated by the only intramolecular stacking pair in the ligand, U7 and U8. All of the nucleotides besides U8 are in the C2’-endo conformation. This orientation allows the bases to be highly exposed to the protein and therefore increases specificity. The low number of intramolecular stacking regions and the large number of C2’-endo conformations deem this ligand unique<ref name="Handa" />.
===RNA binding===
===RNA binding===
-
1. Hydrogen bonding with the RNA backbone:
+
1. Hydrogen bonding with RNA bases:
-
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 <scene name='78/782600/Rrm2_res_bond_to_backbone/1'>Tyr214, Asn241, Arg252, and Arg258</scene>. RRM1 creates two hydrogen bonds with the U9 backbone at <scene name='78/782600/Rrm1_h-bonding_to_backbone/1'>Asn130, Arg155</scene> <ref name="Handa" />.
 
- 
-
2. Hydrogen bonding with RNA bases:
 
There are numerous hydrogen bonds between the residues and the nucleotide bases. RRM2 creates five hydrogen bonds with U3-G4-U5 at residues <scene name='78/782600/Rrm2_res_hbond_w_bases/1'>Asn217, Arg252, Ala289, Asn212, and Gln239</scene>. RRM1 creates nine hydrogen bonds between U6-U7-U8-U9-U10-U11 at residues <scene name='78/782600/Rrm1_res_h-bond_w_bases/3'>Ser165, Arg195, Gly204, Asn126, Gln134, Arg155, Lys197, and Arg202</scene><ref name="Handa" />.
There are numerous hydrogen bonds between the residues and the nucleotide bases. RRM2 creates five hydrogen bonds with U3-G4-U5 at residues <scene name='78/782600/Rrm2_res_hbond_w_bases/1'>Asn217, Arg252, Ala289, Asn212, and Gln239</scene>. RRM1 creates nine hydrogen bonds between U6-U7-U8-U9-U10-U11 at residues <scene name='78/782600/Rrm1_res_h-bond_w_bases/3'>Ser165, Arg195, Gly204, Asn126, Gln134, Arg155, Lys197, and Arg202</scene><ref name="Handa" />.
 +
 +
2. Hydrogen bonding with 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 <scene name='78/782600/Rrm2_res_bond_to_backbone/1'>Tyr214, Asn241, Arg252, and Arg258</scene>. RRM1 creates two hydrogen bonds with the U9 backbone at <scene name='78/782600/Rrm1_h-bonding_to_backbone/1'>Asn130, Arg155</scene> <ref name="Handa" />.
3. Intermolecular stacking:
3. Intermolecular stacking:

Revision as of 23:41, 29 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].


Structure

Sex lethal (PDB: 1B7F)

Drag the structure with the mouse to rotate

Mutation

References

  1. ↑ 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
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 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
  3. ↑ Georgiev P, Chlamydas S, Akhtar A. Drosophila dosage compensation. Fly 2011;5(2):147-154. https://doi.org/10.4161/fly.5.2.14934
  4. ↑ 4.0 4.1 Clery A, Blatter M, Allain FH. RNA recognition motifs: boring? Not quite. Curr Opin Struct Biol. 2008 Jun;18(3):290-8. doi: 10.1016/j.sbi.2008.04.002. PMID:18515081 doi:http://dx.doi.org/10.1016/j.sbi.2008.04.002

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Jeremy C. Caylor

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