Sex-lethal (Sxl) protein/RNA complex
Drosophila melanogaster (fruit fly)
In Drosophila melanogaster the sex is determined according to the ratio of the number of X chromosomes to that of autosomes. The sex-lethal (Sxl) protein regulates alternative splicing, which is a process that produces the mature messenger RNA, of a target RNA precursor during the sex-determination process. The complex structure between the Sxl protein and its target, the transformer (tra) messenger RNA precursor (pre-mRNA) with a uridine rich polypyrimidine sequence, has revealed the mechanism of the sex-determination process in Drosophila melanogaster. It also presents the first insight into the interaction between a protein and a specific RNA which does not involve intramolecular base-pairing.
The Sxl protein contains two RNA-binding domains, each of which contains a beta-sheet structure. These domains face each other and form a V-shaped cleft. The Sxl protein recognizes a specific sequence of the single-stranded pre-mRNA and accommodates it in this cleft. Most RNA-binding proteins recognize intramolecular base-pairs, the stems or loops, on single-stranded RNA. These recognition sites are essential for the RNA-protein interactions. The beta-sheets of the Sxl protein interact not only with the bases but also the phosphate and sugar groups in the polypyrimidine sequence of tra pre-mRNA. In this respect, they differ from other RNA-binding proteins which recognize the stems or loops. Therefore, the Sxl protein recognizes a RNA sequence without the intramolecular base-pairs. In the sex-determination process, tra pre-mRNA undergoes splicing by various splicing factors, e.g. U2AF which binds to specific splice sites of RNAs. The Sxl protein tightly binds to the polypyrimidine sequence at a non-sex-specific splice site in tra pre-mRNA, preventing U2AF from binding to this site and forcing it to bind to the female-specific splice site. The Sxl protein, moreover, binds to its own pre-mRNA to promote the female-specific alternative splicing. Thus, the Sxl protein induces splicing which leads to a female-type individual.
Protein Data Bank (PDB)
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) 398:579-585 PubMed:10217141.
author: Yuko Tsuchiya