Srp20-Human Alternative Splicing Factor: Difference between revisions

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== Overview ==
== Overview ==
The SRp20 protein is an alternative splicing factor for several genes found in homo sapiens as well as many other [https://en.wikipedia.org/wiki/Eukaryote eukaryotes]. [[Image:AASequence.jpg|350px|right|thumb|'''Figure 1.''' SRp20 Domain Representation. Shown are the RRM (green), the TAP binding linker (red line) and SR-rich domain (blue).]] It is a relatively small protein with a length of 164 amino acids and a weight of about 19kDa. In fact, it is the smallest member of the SR protein family. The protein contains two domains: a serine-arginine rich (SR) domain which includes the RNA bound ligand and a RNA-recognition motif (RRM) although only a 3D image of the RRM structure is presented here <ref name="Corbo2013">PMID:23685143</ref>.  
The SRp20 protein is an alternative splicing factor for several genes found in homo sapiens as well as many other [https://en.wikipedia.org/wiki/Eukaryote eukaryotes]. [[Image:AASequence.jpg|350px|right|thumb|'''Figure 1.''' SRp20 Domain Representation. Shown are the RRM (green), the TAP binding linker (red line) and SR-rich domain (blue).]] It is a relatively small protein with a length of 164 amino acids and a weight of about 19kDa. In fact, it is the smallest member of the SR protein family. The protein contains two domains: a serine-arginine rich (SR) domain and a RNA-recognition motif (RRM) that includes the RNA bound ligand; unfortunately, only a 3D image of the RRM structure is presented here due to solubility issues <ref name="Corbo2013">PMID:23685143</ref>.  


== Introduction ==
== Introduction ==
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Splicing is one step in the process of RNA maturation that cuts out introns and joins exons together.  Both the spliceosome, a complex of snRNAs (U1, U2, etc.), and splicing factors like SRp20 interact with intron consensus sequences in the pre-mRNA to regulate this process. [https://en.wikipedia.org/wiki/Alternative_splicing Alternative splicing] allows one mRNA molecule to produce numerous proteins that perform different functions in a cell by inclusion and exclusion of RNA sequences. There are two main families of splicing factors: Serine-Arginine rich (SR) proteins and heterogeneous nuclear RiboNucleoProteins ([https://en.wikipedia.org/wiki/Heterogeneous_ribonucleoprotein_particle hnRNPs]).  
Splicing is one step in the process of RNA maturation that cuts out introns and joins exons together.  Both the spliceosome, a complex of snRNAs (U1, U2, etc.), and splicing factors like SRp20 interact with intron consensus sequences in the pre-mRNA to regulate this process. [https://en.wikipedia.org/wiki/Alternative_splicing Alternative splicing] allows one mRNA molecule to produce numerous proteins that perform different functions in a cell by inclusion and exclusion of RNA sequences. There are two main families of splicing factors: Serine-Arginine rich (SR) proteins and heterogeneous nuclear RiboNucleoProteins ([https://en.wikipedia.org/wiki/Heterogeneous_ribonucleoprotein_particle hnRNPs]).  
The SRp20 protein belongs to the SR protein family. All SR proteins are defined by a RNA-binding domain at the N-terminus and a serine-arginine rich domain at the C-terminus<ref name="Zahler">PMID:1577277</ref>. The discovery of this family started in the 1900s with the [https://en.wikipedia.org/wiki/Serine/arginine-rich_splicing_factor_1 SF2] (SRp30a) protein and has since come to include twelve proteins, all of which act as splicing factors. SRp20 was first discovered in calf thymus when it was separated with several other SR proteins based on their molecular weight<ref name="Zahler">PMID:1577277</ref>.  
The SRp20 protein belongs to the SR protein family. All SR proteins are defined by a RNA-binding domain at the N-terminus and a serine-arginine rich domain at the C-terminus<ref name="Zahler">PMID:1577277</ref>. The discovery of this family started in the 1900s with the [https://en.wikipedia.org/wiki/Serine/arginine-rich_splicing_factor_1 SF2] (SRp30a) protein and has since come to include twelve proteins, all of which act as splicing factors. SRp20 was first discovered in calf thymus when it was separated with several other SR proteins based on their molecular weight<ref name="Zahler">PMID:1577277</ref>.  
An identical protein, called [http://www.uniprot.org/uniprot/Q9V3V0 X16], was discovered in an earlier paper studying different genes that change expression during [https://en.wikipedia.org/wiki/B_cell B-cell] development<ref name="Corbo2013">PMID:23685143</ref>. At the time, the protein was assumed to play a role in RNA processing and cellular proliferation, a finding that was later proved to be true<ref name="Ayane">PMID:2030943</ref><ref name="Cacero">PMID:11932019</ref>.  
The SRp20 protein, called [http://www.uniprot.org/uniprot/Q9V3V0 X16] originally, was actually discovered first in an earlier paper studying different genes that change expression during [https://en.wikipedia.org/wiki/B_cell B-cell] development<ref name="Corbo2013">PMID:23685143</ref>. At the time, the protein was assumed to play a role in RNA processing and cellular proliferation, a finding that was later proved in further studies<ref name="Ayane">PMID:2030943</ref><ref name="Cacero">PMID:11932019</ref>.  
The SRp20 protein has been shown to play a role in cancer progression and neurological disorders, specifically through alternative splicing. For example, SRp20 has been shown to play a role in alternative splicing of the Tau protein, an integral protein in the progression of Alzheimer’s disease<ref name="Corbo2013">PMID:23685143</ref>. SRp20 has even been found to serve as a splicing factor for its own mRNA, influencing the inclusion of exon 4<ref name="Corbo2013">PMID:23685143</ref>. Another function of SRp20 is its role in export of mRNA out of the nucleus, notably [https://en.wikipedia.org/wiki/Histone_H2A H2A histone] mRNA export<ref name="Hargous">PMID:17036044</ref>.
The SRp20 protein has been shown to play a role in cancer progression and neurological disorders, specifically through alternative splicing. For example, SRp20 has been shown to play a role in alternative splicing of the Tau protein, an integral protein in the progression of Alzheimer’s disease<ref name="Corbo2013">PMID:23685143</ref>. SRp20 has even been found to serve as a splicing factor for its own mRNA, influencing the inclusion of exon 4<ref name="Corbo2013">PMID:23685143</ref>. Another function of SRp20 is its role in export of mRNA out of the nucleus, notably [https://en.wikipedia.org/wiki/Histone_H2A H2A histone] mRNA export<ref name="Hargous">PMID:17036044</ref>.
== Structure and Function ==
== Structure and Function ==
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=== Splicing Activity ===
=== Splicing Activity ===
The splicing mechanism for SRp20 follows the normal eukaryotic mechanism, in which five different [https://en.wikipedia.org/wiki/SnRNP small nuclear ribonucleoproteins] (snRNPs) bring the splice sites together in order to start the reaction ('''Figure 2'''). Specifically, SRp20 and other SR proteins interact with the RNA ligand at the [https://en.wikipedia.org/wiki/Exonic_splicing_enhancer exonic splicing enhancer sequence] at the beginning of the 3’ splice site adjacent to the intron being removed. SRp20 facilitates the interaction of the U2 snRNP with the RNA to continue the mechanism ('''Figure 3''')<ref name="Shepard">PMID:19857271</ref>. [[Image:mechanism1.png|300px|left|thumb|'''Figure 2.''' Splicing mechanism for eukaryotes. Free 3’OH nucleophile of adenosine in intron attacks phosphorus of phosphate creating a ring structure intron known as a lariat. The free 2’OH in the 5’ splice site (red) acts as the nucleophile to attack the phosphate of the first nucleotide in the 3’ splice site (red) to release the [https://news.brown.edu/articles/2012/06/lariats lariat] intron. The products include the final modified RNA sequence and the lariat which will be recycled.]] [[Image:prettymechanism.png|260px|right|thumb|'''Figure 3.''' SRp20 works with [https://en.wikipedia.org/wiki/U2_spliceosomal_RNA U2] snRNP: Five snRNPs are needed in the eukaryotic splicing mechanism to facilitate the reaction. The U2 snRNP must attach to the 3’ splice site to bring together the 5’ and 3’ splice sites (red). SRp20 facilitates binding of U2 to the 3’ splice site by binding to the exonic splicing enhancer sequence (blue) in the RNA at the backbone. U2 must bind before the other snRNPs can bind to continue the mechanism.]]
The splicing mechanism for SRp20 follows the normal eukaryotic mechanism, in which five different [https://en.wikipedia.org/wiki/SnRNP small nuclear ribonucleoproteins] (snRNPs) bring the splice sites together in order to start the reaction. The free 3’OH nucleophile of adenosine in the intron attacks the phosphorus of phosphate creating a ring structure intron known as a [https://news.brown.edu/articles/2012/06/lariats lariat]. The free 2’OH in the 5’ splice site acts as the nucleophile to attack the phosphate of the first nucleotide in the 3’ splice site to release the lariat intron ('''Figure 2'''). Specifically, SRp20 and other SR proteins interact with the RNA ligand at the [https://en.wikipedia.org/wiki/Exonic_splicing_enhancer exonic splicing enhancer sequence] at the beginning of the 3’ splice site adjacent to the intron being removed. SRp20 facilitates the interaction of the U2 snRNP with the RNA to continue the mechanism ('''Figure 3''')<ref name="Shepard">PMID:19857271</ref>. [[Image:mechanism1.png|300px|left|thumb|'''Figure 2.''' Splicing mechanism for eukaryotes. The products include the final modified RNA sequence and the lariat which will be recycled.]] [[Image:prettymechanism.png|260px|right|thumb|'''Figure 3.''' SRp20 works with [https://en.wikipedia.org/wiki/U2_spliceosomal_RNA U2] snRNP: Five snRNPs are needed in the eukaryotic splicing mechanism to facilitate the reaction.]]




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