User:Laurine Seltz/Sandbox 1
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Gemin5 pre-snRNA
Context
During the phenomenon of splicing and the assembly of the exons in the eukaryotes cells, there are some important complexes that are needed: the spliceosomes which are formed of snRNPs (small nuclear ribonucleoprotein particles). These particles are produced due to interaction between the Sm core protein and some small nuclear RNA, regulated by the complex of the survival of motor neurons that works as a chaperone. This last complex is composed of three proteins, the SMN, Unrip and the proteins Gemin2 to Gemin8.
Function
Gemin5 regulated the specificity that chooses the snRNA precursors and make the transition to the Sm proteins. In others words, it’s helped to generate the spliceosome complex. The specificity of Gemin5 is due to two binding on different sequences on the Sm core protein:
Structure
The apo form of Gemin5 shows 14 WD motifs able to fold into 2 connected seven-bladed β-propellers. The first doughnut-shaped propeller is called WD1 and is composed of blades 1 to 7 corresponding to the amino acids 19 to 377. The second is called WD2, composed of blades 8 to 14 corresponding to the amino acids 428 to 712. They are very similar in size, with around 38 Å in diameter, around 55 Å high and twisted around 15° askew relative to one another. The N-terminal region of WD1 forms the outermost β-strand of blade 14 in WD2. This structural motif is said to be referred to a “molecular velcro”, also found in the structure of Aip1.
The WD-40 motif is also known as WD or beta-transducin. It is a short motif which contains around 40 amino acids and often ended with the Trp-Asp, or W-D, amino acids. Most of the time, WD-40 motifs folded into a 7-8 bladed beta-propeller. Proteins containing WD motifs exist in all eukaryotes and have different functions. Repeated WD-40 motifs are a site for protein-protein interactions and it had been shown that they act as platforms for the assembly of protein complexes. The specificity of the recognition is based on the sequences outside the repeats. Here are some examples of proteins which contains such a motif : E3 ubiquitin ligase [(PUBMED:11814058), (PUBMED:10322433)], TAFII transcription factor, beta subunit of G proteins.
Interactions
The way of working of the protein is based on a lot of interactions. For instance between the SmRNA and WD1 and WD2. Indeed the blade 14 is linked to the 3’ of the SmRNA and makes a lot of interactions with WD1. On the other side, the 5’ side of the SmRNA, we find the blade 8 that contains Trip 422 and EWD2. Moreover it contains Trp14 which directly stacks againts U5, which stacks itself agains U6. Arg359, Arg33 ans Asm 13 also stack against U6. Asm recognizes a base of U6. On the same model, The terminal nucleobase of U7 stacks against Phe382 and WD40 domain of DDB2 recognizes dsDNA. Trp286 is located in a hydrophobic core of blade of WD1, contacting Tyr15 which stacks against the flipped nucleotide of U6. SmRNA is recognized through 2 grooves formed on either side of Tyr15 in WD1 and Tyr15 stacks against a flipped nucleotide of U4. Moreover 5’ is linked to blades 7 and 8, that helds nucleotides U3 and A2. Indeed A2 abd U3 are attached by hydrogen bonds because of the guanidinium group of Arg333 which is between A2 and U3. They stack against each other as well as A1. bTo further characterize the role of residues involved in SmRNA binding we mutated several conserved residues in Gemin5-WD, wich allowed us to get these results. It allows a real connection between all thoses parts.
Disease
The SMN plays an important role and its deficiency can tend to a degenerative disease linked with the motor neurons. It’s called the SMA (spinal muscular atrophy) and made a dysfunction in the expression of SMN1 that coded for the synthesis of the protein of the SMN complex. It’s the second common recessive disease after cystic fibrosis. The death of neurons cause a paralysis of some member and weakness in every muscle of the body. The disease can occurred with four different ways: -Type I, it’s the most extreme form of the disease that is diagnostic at birth, the patient have no hope of living, life expectancy: 2 years. The child are not able to sit or to walk -Type II, possible to detect it since 6 months, characterized by an incapacity to walk independently but they can sit. -Type III, last juvenile form, less consequences than in the two other forms, can do both of the activities without help.
Structural highlights
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