SnRNP
Encyclopedia
snRNPs or small nuclear ribonucleoproteins, are RNA
-protein complexes that combine with unmodified pre-mRNA and various other proteins to form a spliceosome
, a large RNA-protein molecular complex upon which splicing
of pre-mRNA occurs. The action of snRNPs is essential to the removal of introns from pre-mRNA, a critical aspect of post-transcriptional modification
of RNA, occurring only in the nucleus
of eukaryotic cells
.
The two essential components of snRNPs are protein
molecules and RNA
. The RNA found within each snRNP particle is known as small nuclear RNA, or snRNA, and is usually about 150 nucleotides in length. The snRNA component of the snRNP gives specificity to individual introns by "recognizing
" the sequences of critical splicing signals at the 5' and 3' ends and branch site of introns. The snRNA in snRNPs is similar to ribosomal RNA
in that it directly incorporates both an enzymatic and a structural role.
SnRNPs were discovered by Michael R. Lerner and Joan A. Steitz
.
Thomas R. Cech and Sidney Altman also played a role in the discovery, winning the Nobel Prize for Chemistry in 1989 for their independent discoveries that RNA can act as a catalyst in cell development (http://www.colorado.edu/news/nobel/cech/).
. They can be visualized by gel electrophoresis
and are known individually as: U1, U2, U4, U5, and U6. Their snRNA components are known, respectively, as: U1 snRNA, U2 snRNA, U4 snRNA, U5 snRNA, and U6 snRNA.
In the mid-1990s, it was discovered that a variant class of snRNPs exists to help in the splicing of a class of introns found only in metazoans, with highly-conserved 5' splice sites and branch sites. This variant class of snRNPs includes: U11 snRNA, U12 snRNA, U4atac snRNA
, and U6atac snRNA
. While different, they perform the same functions as do U1, U2, U4, and U6, respectively.
and cytoplasm
.
transcribes U1, U2, U4, U5 and the less abundant U11, U12 and U4atac (snRNAs
) acquire a m7G-cap which serves as export signal. Nuclear export is mediated by CRM1.
are synthesized in the cytoplasm by ribosomes translating Sm messenger RNA
, just like any other protein. These are stored in the cytoplasm in the form of three partially assembled rings complexes all associated with the pICln protein. They are a 6S pentamer complex of SmD1,SmD2, SmF, SmE and SmG with pICln, a 2-4S complex of B, possibly with D3 and pICln and the 20S methylosome, which is a large complex of SmD3, SmB, SmD1, pICln and the arginine methyltransferase-5 (PRMT5) protein. SmD3, SmB and SmD1 undergo post-translational modification
in the methylosome. These three Sm proteins have repeated arginine
-glycine
motifs in the C-terminal end
s of SmD1, SmD3 and SmB, and the arginine side chains are symmetrically dimethylated to ω-NG, NG'-dimethyl-arginine. It has been suggested that pICln, which occurs in all three precursor complexes but is absent in the mature snRNPs, acts as a specialized chaperone, preventing premature assembly of Sm proteins.
(U1, U2, U4, U5, and the less abundant U11, U12 and U4atac) quickly interact with the SMN (Survival of Motor Neurons) protein and other proteins (Gemins 2-8) forming the large SMN complex. It is here that the snRNA binds to the SmD1-SmD2-SmF-SmE-SmG pentamer, followed by addition of the SmD3-SmB dimer to complete the Sm ring around the so-called Sm site of the snRNA. This Sm site is a conserved sequence of nucleotides in these snRNAs, typically AUUUGUGG (where A, U and G represent the nucleosides adenosine, uridine
and guanosine
respectively). After assembly of the Sm ring around the snRNA, the 5' terminal nucleoside (already modified to a 7-methylguanosine cap) is hyper-methylated to 2,2,7-trimethylguanosine and the other (3') end of the snRNA is trimmed. This modification, and the presence of a complete Sm ring, is recognized by the snurportin 1 protein.
, where final assembly of the snRNPs take place. This consists of additional proteins and other modifications specific to the particular snRNP (U1, U2, U4, U5). The biogenesis of the U6 snRNP occurs in the nucleus although large amounts of free U6 are found in the cytoplasm. The LSm
ring may assemble first, and then associate with the U6 snRNA.
are associated with premature death of spinal motor neuron
s, and results in Spinal muscular atrophy
(SMA). This genetic disease
is manifested over a wide range of severity. The most severe form results in paralysis, is usually fatal by age 2, and is the most common genetic cause of infant death.
(SLE).
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
-protein complexes that combine with unmodified pre-mRNA and various other proteins to form a spliceosome
Spliceosome
A spliceosome is a complex of snRNA and protein subunits that removes introns from a transcribed pre-mRNA segment. This process is generally referred to as splicing.-Composition:...
, a large RNA-protein molecular complex upon which splicing
RNA splicing
In molecular biology and genetics, splicing is a modification of an RNA after transcription, in which introns are removed and exons are joined. This is needed for the typical eukaryotic messenger RNA before it can be used to produce a correct protein through translation...
of pre-mRNA occurs. The action of snRNPs is essential to the removal of introns from pre-mRNA, a critical aspect of post-transcriptional modification
Post-transcriptional modification
Post-transcriptional modification is a process in cell biology by which, in eukaryotic cells, primary transcript RNA is converted into mature RNA. A notable example is the conversion of precursor messenger RNA into mature messenger RNA , which includes splicing and occurs prior to protein synthesis...
of RNA, occurring only in the nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
of eukaryotic cells
Eukaryote
A eukaryote is an organism whose cells contain complex structures enclosed within membranes. Eukaryotes may more formally be referred to as the taxon Eukarya or Eukaryota. The defining membrane-bound structure that sets eukaryotic cells apart from prokaryotic cells is the nucleus, or nuclear...
.
The two essential components of snRNPs are protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
molecules and RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
. The RNA found within each snRNP particle is known as small nuclear RNA, or snRNA, and is usually about 150 nucleotides in length. The snRNA component of the snRNP gives specificity to individual introns by "recognizing
Complementarity
-Mathematics:*Complementary angles, in geometry* Complementarity theory, a concept related to optimization -Physical sciences:* Complementarity , a property of nucleic acid molecules in molecular biology...
" the sequences of critical splicing signals at the 5' and 3' ends and branch site of introns. The snRNA in snRNPs is similar to ribosomal RNA
Ribosomal RNA
Ribosomal ribonucleic acid is the RNA component of the ribosome, the enzyme that is the site of protein synthesis in all living cells. Ribosomal RNA provides a mechanism for decoding mRNA into amino acids and interacts with tRNAs during translation by providing peptidyl transferase activity...
in that it directly incorporates both an enzymatic and a structural role.
SnRNPs were discovered by Michael R. Lerner and Joan A. Steitz
Joan A. Steitz
Joan Argetsinger Steitz is a molecular biologist at Yale University, famed for her discoveries involving RNA, including ground-breaking insights such as that ribosomes interact with mRNA by complementary base pairing and that introns are spliced by snRNPs, small nuclear ribonucleoproteins which...
.
Thomas R. Cech and Sidney Altman also played a role in the discovery, winning the Nobel Prize for Chemistry in 1989 for their independent discoveries that RNA can act as a catalyst in cell development (http://www.colorado.edu/news/nobel/cech/).
Types of snRNPs
At least five different kinds of snRNPs join the spliceosome to participate in splicingSplicing (genetics)
In molecular biology and genetics, splicing is a modification of an RNA after transcription, in which introns are removed and exons are joined. This is needed for the typical eukaryotic messenger RNA before it can be used to produce a correct protein through translation...
. They can be visualized by gel electrophoresis
Gel electrophoresis
Gel electrophoresis is a method used in clinical chemistry to separate proteins by charge and or size and in biochemistry and molecular biology to separate a mixed population of DNA and RNA fragments by length, to estimate the size of DNA and RNA fragments or to separate proteins by charge...
and are known individually as: U1, U2, U4, U5, and U6. Their snRNA components are known, respectively, as: U1 snRNA, U2 snRNA, U4 snRNA, U5 snRNA, and U6 snRNA.
In the mid-1990s, it was discovered that a variant class of snRNPs exists to help in the splicing of a class of introns found only in metazoans, with highly-conserved 5' splice sites and branch sites. This variant class of snRNPs includes: U11 snRNA, U12 snRNA, U4atac snRNA
U4atac minor spliceosomal RNA
U4atac minor spliceosomal RNA is a ncRNA which is an essential component of the minor U12-type spliceosome complex. The U12-type spliceosome is required for removal of the rarer class of eukaryotic introns ....
, and U6atac snRNA
U6atac minor spliceosomal RNA
U6atac minor spliceosomal RNA is a non-coding RNA which is an essential component of the minor U12-type spliceosome complex. The U12-type spliceosome is required for removal of the rarer class of eukaryotic introns ....
. While different, they perform the same functions as do U1, U2, U4, and U6, respectively.
Biogenesis
Small nuclear ribonucleoproteins (snRNPs) assemble in a tightly orchestrated and regulated process that involves both the cell nucleusCell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
and cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
.
Synthesis and export of RNA in the nucleus
The RNA polymerase IIRNA polymerase II
RNA polymerase II is an enzyme found in eukaryotic cells. It catalyzes the transcription of DNA to synthesize precursors of mRNA and most snRNA and microRNA. A 550 kDa complex of 12 subunits, RNAP II is the most studied type of RNA polymerase...
transcribes U1, U2, U4, U5 and the less abundant U11, U12 and U4atac (snRNAs
Non-coding RNA
A non-coding RNA is a functional RNA molecule that is not translated into a protein. Less-frequently used synonyms are non-protein-coding RNA , non-messenger RNA and functional RNA . The term small RNA is often used for short bacterial ncRNAs...
) acquire a m7G-cap which serves as export signal. Nuclear export is mediated by CRM1.
Synthesis and storage of Sm proteins in the cytoplasm
The Sm proteinsLSm
In biology, LSm proteins are a family of RNA-binding proteins found in virtually every cellular organism. LSm is a contraction of 'like Sm', because the first identified members of the LSm protein family were the Sm proteins...
are synthesized in the cytoplasm by ribosomes translating Sm messenger RNA
Messenger RNA
Messenger RNA is a molecule of RNA encoding a chemical "blueprint" for a protein product. mRNA is transcribed from a DNA template, and carries coding information to the sites of protein synthesis: the ribosomes. Here, the nucleic acid polymer is translated into a polymer of amino acids: a protein...
, just like any other protein. These are stored in the cytoplasm in the form of three partially assembled rings complexes all associated with the pICln protein. They are a 6S pentamer complex of SmD1,SmD2, SmF, SmE and SmG with pICln, a 2-4S complex of B, possibly with D3 and pICln and the 20S methylosome, which is a large complex of SmD3, SmB, SmD1, pICln and the arginine methyltransferase-5 (PRMT5) protein. SmD3, SmB and SmD1 undergo post-translational modification
Posttranslational modification
Posttranslational modification is the chemical modification of a protein after its translation. It is one of the later steps in protein biosynthesis, and thus gene expression, for many proteins....
in the methylosome. These three Sm proteins have repeated arginine
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
-glycine
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...
motifs in the C-terminal end
C-terminal end
The C-terminus is the end of an amino acid chain , terminated by a free carboxyl group . When the protein is translated from messenger RNA, it is created from N-terminus to C-terminus...
s of SmD1, SmD3 and SmB, and the arginine side chains are symmetrically dimethylated to ω-NG, NG'-dimethyl-arginine. It has been suggested that pICln, which occurs in all three precursor complexes but is absent in the mature snRNPs, acts as a specialized chaperone, preventing premature assembly of Sm proteins.
Assembly of core snRNPs in the SMN complex
The snRNAsNon-coding RNA
A non-coding RNA is a functional RNA molecule that is not translated into a protein. Less-frequently used synonyms are non-protein-coding RNA , non-messenger RNA and functional RNA . The term small RNA is often used for short bacterial ncRNAs...
(U1, U2, U4, U5, and the less abundant U11, U12 and U4atac) quickly interact with the SMN (Survival of Motor Neurons) protein and other proteins (Gemins 2-8) forming the large SMN complex. It is here that the snRNA binds to the SmD1-SmD2-SmF-SmE-SmG pentamer, followed by addition of the SmD3-SmB dimer to complete the Sm ring around the so-called Sm site of the snRNA. This Sm site is a conserved sequence of nucleotides in these snRNAs, typically AUUUGUGG (where A, U and G represent the nucleosides adenosine, uridine
Uridine
Uridine is a molecule that is formed when uracil is attached to a ribose ring via a β-N1-glycosidic bond.If uracil is attached to a deoxyribose ring, it is known as a deoxyuridine....
and guanosine
Guanosine
Guanosine is a purine nucleoside comprising guanine attached to a ribose ring via a β-N9-glycosidic bond. Guanosine can be phosphorylated to become guanosine monophosphate , cyclic guanosine monophosphate , guanosine diphosphate , and guanosine triphosphate...
respectively). After assembly of the Sm ring around the snRNA, the 5' terminal nucleoside (already modified to a 7-methylguanosine cap) is hyper-methylated to 2,2,7-trimethylguanosine and the other (3') end of the snRNA is trimmed. This modification, and the presence of a complete Sm ring, is recognized by the snurportin 1 protein.
Final assembly of the snRNPs in the nucleus
The completed core snRNP-snurportin 1 complex is transported into the nucleus via the protein importin β. Inside the nucleus, the core snRNPs appear in the Cajal bodiesCajal body
Cajal bodies are spherical sub-organelles of 0.3-1.0 µm in diameter found in the nucleus of proliferative cells like embryonic cells and tumor cells, or metabolically active cells like neurons. In contrast to cytoplasmic organelles, CBs lack any phospholipid membrane which would separate their...
, where final assembly of the snRNPs take place. This consists of additional proteins and other modifications specific to the particular snRNP (U1, U2, U4, U5). The biogenesis of the U6 snRNP occurs in the nucleus although large amounts of free U6 are found in the cytoplasm. The LSm
LSm
In biology, LSm proteins are a family of RNA-binding proteins found in virtually every cellular organism. LSm is a contraction of 'like Sm', because the first identified members of the LSm protein family were the Sm proteins...
ring may assemble first, and then associate with the U6 snRNA.
Disassembly of snRNPs
The snRNPs are very long-lived, but are assumed to be eventually disassembled and degraded. Nothing is known about this process...yet.Defects in snRNP biogenesis as a cause of Spinal muscular atrophy
Defects in the SMN geneGene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
are associated with premature death of spinal motor neuron
Motor neuron
In vertebrates, the term motor neuron classically applies to neurons located in the central nervous system that project their axons outside the CNS and directly or indirectly control muscles...
s, and results in Spinal muscular atrophy
Spinal muscular atrophy
Spinal Muscular Atrophy is a neuromuscular disease characterized by degeneration of motor neurons, resulting in progressive muscular atrophy and weakness. The clinical spectrum of SMA ranges from early infant death to normal adult life with only mild weakness...
(SMA). This genetic disease
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
is manifested over a wide range of severity. The most severe form results in paralysis, is usually fatal by age 2, and is the most common genetic cause of infant death.
Anti-snRNP antibodies
Autoantibodies may be produced against the body's own snRNPs, most notably the anti-Sm antibodies targeted against the Sm protein type of snRNP specifically in systemic lupus erythematosusSystemic lupus erythematosus
Systemic lupus erythematosus , often abbreviated to SLE or lupus, is a systemic autoimmune disease that can affect any part of the body. As occurs in other autoimmune diseases, the immune system attacks the body's cells and tissue, resulting in inflammation and tissue damage...
(SLE).