SnRNP

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snRNPs (pronounced "snurps"), 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. Additionally, U7 snRNP is not involved in splicing at all, as U7 snRNP is responsible for processing the 3′ stem-loop of histone pre-mRNA. [1]

Contents

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. [2] [3] 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.

Types

At least five different kinds of snRNPs join the spliceosome to participate in splicing. 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. [4]

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. [5]

Additionally, U7 snRNP is made of U7 small nuclear RNA and associated proteins and is involved in the processing of the 3′ stem-loop of histone pre-mRNA. [1]

Biogenesis

Small nuclear ribonucleoproteins (snRNPs) assemble in a tightly orchestrated and regulated process that involves both the cell nucleus and cytoplasm. [6]

Synthesis and export of RNA in the nucleus

The RNA polymerase II transcribes U1, U2, U4, U5 and the less abundant U11, U12 and U4atac (snRNAs) acquire a m7G-cap which serves as an export signal. Nuclear export is mediated by CRM1.

Synthesis and storage of Sm proteins in the cytoplasm

The Sm proteins 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 SmB, possibly with SmD3 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. [7] These three Sm proteins have repeated arginine-glycine motifs in the C-terminal ends 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 snRNAs (U1, U2, U4, U5, and the less abundant U11, U12 and U4atac) quickly interact with the SMN (survival of motor neuron protein); encoded by SMN1 gene) and Gemins 2-8 (Gem-associated proteins: GEMIN2, GEMIN3, GEMIN4, GEMIN5, GEMIN6, GEMIN7, GEMIN8) forming the SMN complex. [8] [9] 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.

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 bodies, 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.

Disassembly of snRNPs

The snRNPs are very long-lived, but are assumed to be eventually disassembled and degraded. Little is known about the degradation process.

Defective assembly

Defective function of the survival of motor neuron (SMN) protein in snRNP biogenesis, caused by a genetic defect in the SMN1 gene which codes for SMN, may account for the motor neuron pathology observed in the genetic disorder spinal muscular atrophy. [10]

Structures, function and organization

Several human and yeast snRNP structures were determined by the cryo-electron microscopy and successive single particle analysis. [11] Recently, the human U1 snRNP core structure was determined by X-ray crystallography (3CW1, 3PGW), followed by a structure of the U4 core snRNP (2Y9A), which yielded first insights into atomic contacts, especially the binding mode of the Sm proteins to the Sm site. The structure of U6 UsnRNA was solved in complex with a specific protein Prp24 (4N0T), as well as a structure of its 3'-nucleotides bound to the special Lsm2-8 protein ring (4M7A). The PDB codes for the respective structures are mentioned in parentheses. [12] [13] The structures determined by single particle electron microscopy analysis are: human U1 snRNP, [14] human U11/U12 di-snRNP, [15] human U5 snRNP, U4/U6 di-snRNP, U4/U6∙U5 tri-snRNP. [16] The further progress determining the structures and functions of snRNPs and spliceosomes continues. [17]

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 erythematosus (SLE).

Related Research Articles

<span class="mw-page-title-main">RNA splicing</span> Process in molecular biology

RNA splicing is a process in molecular biology where a newly-made precursor messenger RNA (pre-mRNA) transcript is transformed into a mature messenger RNA (mRNA). It works by removing all the introns and splicing back together exons. For nuclear-encoded genes, splicing occurs in the nucleus either during or immediately after transcription. For those eukaryotic genes that contain introns, splicing is usually needed to create an mRNA molecule that can be translated into protein. For many eukaryotic introns, splicing occurs in a series of reactions which are catalyzed by the spliceosome, a complex of small nuclear ribonucleoproteins (snRNPs). There exist self-splicing introns, that is, ribozymes that can catalyze their own excision from their parent RNA molecule. The process of transcription, splicing and translation is called gene expression, the central dogma of molecular biology.

<span class="mw-page-title-main">Spliceosome</span> Molecular machine that removes intron RNA from the primary transcript

A spliceosome is a large ribonucleoprotein (RNP) complex found primarily within the nucleus of eukaryotic cells. The spliceosome is assembled from small nuclear RNAs (snRNA) and numerous proteins. Small nuclear RNA (snRNA) molecules bind to specific proteins to form a small nuclear ribonucleoprotein complex, which in turn combines with other snRNPs to form a large ribonucleoprotein complex called a spliceosome. The spliceosome removes introns from a transcribed pre-mRNA, a type of primary transcript. This process is generally referred to as splicing. An analogy is a film editor, who selectively cuts out irrelevant or incorrect material from the initial film and sends the cleaned-up version to the director for the final cut.

Small nuclear RNA (snRNA) is a class of small RNA molecules that are found within the splicing speckles and Cajal bodies of the cell nucleus in eukaryotic cells. The length of an average snRNA is approximately 150 nucleotides. They are transcribed by either RNA polymerase II or RNA polymerase III. Their primary function is in the processing of pre-messenger RNA (hnRNA) in the nucleus. They have also been shown to aid in the regulation of transcription factors or RNA polymerase II, and maintaining the telomeres.

<span class="mw-page-title-main">Minor spliceosome</span>

The minor spliceosome is a ribonucleoprotein complex that catalyses the removal (splicing) of an atypical class of spliceosomal introns (U12-type) from messenger RNAs in some clades of eukaryotes. This process is called noncanonical splicing, as opposed to U2-dependent canonical splicing. U12-type introns represent less than 1% of all introns in human cells. However they are found in genes performing essential cellular functions.

<span class="mw-page-title-main">LSm</span> Family of RNA-binding proteins

In molecular 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. LSm proteins are defined by a characteristic three-dimensional structure and their assembly into rings of six or seven individual LSm protein molecules, and play a large number of various roles in mRNA processing and regulation.

<span class="mw-page-title-main">U11 spliceosomal RNA</span> Non-coding RNA involved in alternative splicing

The U11 snRNA is an important non-coding RNA in the minor spliceosome protein complex, which activates the alternative splicing mechanism. The minor spliceosome is associated with similar protein components as the major spliceosome. It uses U11 snRNA to recognize the 5' splice site while U12 snRNA binds to the branchpoint to recognize the 3' splice site.

<span class="mw-page-title-main">U1 spliceosomal RNA</span>

U1 spliceosomal RNA is the small nuclear RNA (snRNA) component of U1 snRNP, an RNA-protein complex that combines with other snRNPs, unmodified pre-mRNA, and various other proteins to assemble a spliceosome, a large RNA-protein molecular complex upon which splicing of pre-mRNA occurs. Splicing, or the removal of introns, is a major aspect of post-transcriptional modification, and takes place only in the nucleus of eukaryotes.

<span class="mw-page-title-main">U2 spliceosomal RNA</span>

U2 spliceosomal snRNAs are a species of small nuclear RNA (snRNA) molecules found in the major spliceosomal (Sm) machinery of virtually all eukaryotic organisms. In vivo, U2 snRNA along with its associated polypeptides assemble to produce the U2 small nuclear ribonucleoprotein (snRNP), an essential component of the major spliceosomal complex. The major spliceosomal-splicing pathway is occasionally referred to as U2 dependent, based on a class of Sm intron—found in mRNA primary transcripts—that are recognized exclusively by the U2 snRNP during early stages of spliceosomal assembly. In addition to U2 dependent intron recognition, U2 snRNA has been theorized to serve a catalytic role in the chemistry of pre-RNA splicing as well. Similar to ribosomal RNAs (rRNAs), Sm snRNAs must mediate both RNA:RNA and RNA:protein contacts and hence have evolved specialized, highly conserved, primary and secondary structural elements to facilitate these types of interactions.

<span class="mw-page-title-main">U4 spliceosomal RNA</span> Non-coding RNA component of the spliceosome

The U4 small nuclear Ribo-Nucleic Acid is a non-coding RNA component of the major or U2-dependent spliceosome – a eukaryotic molecular machine involved in the splicing of pre-messenger RNA (pre-mRNA). It forms a duplex with U6, and with each splicing round, it is displaced from the U6 snRNA in an ATP-dependent manner, allowing U6 to re-fold and create the active site for splicing catalysis. A recycling process involving protein Brr2 releases U4 from U6, while protein Prp24 re-anneals U4 and U6. The crystal structure of a 5′ stem-loop of U4 in complex with a binding protein has been solved.

<span class="mw-page-title-main">U5 spliceosomal RNA</span>

U5 snRNA is a small nuclear RNA (snRNA) that participates in RNA splicing as a component of the spliceosome. It forms the U5 snRNP by associating with several proteins including Prp8 - the largest and most conserved protein in the spliceosome, Brr2 - a helicase required for spliceosome activation, Snu114, and the 7 Sm proteins. U5 snRNA forms a coaxially-stacked series of helices that project into the active site of the spliceosome. Loop 1, which caps this series of helices, forms 4-5 base pairs with the 5'-exon during the two chemical reactions of splicing. This interaction appears to be especially important during step two of splicing, exon ligation.

<span class="mw-page-title-main">U6 spliceosomal RNA</span> Small nuclear RNA component of the spliceosome

U6 snRNA is the non-coding small nuclear RNA (snRNA) component of U6 snRNP, an RNA-protein complex that combines with other snRNPs, unmodified pre-mRNA, and various other proteins to assemble a spliceosome, a large RNA-protein molecular complex that catalyzes the excision of introns from pre-mRNA. Splicing, or the removal of introns, is a major aspect of post-transcriptional modification and takes place only in the nucleus of eukaryotes.

<span class="mw-page-title-main">U7 small nuclear RNA</span>

The U7 small nuclear RNA is an RNA molecule and a component of the small nuclear ribonucleoprotein complex. The U7 snRNA is required for histone pre-mRNA processing.

<span class="mw-page-title-main">Small Cajal body-specific RNA</span>

Small Cajal body-specific RNAs (scaRNAs) are a class of small nucleolar RNAs (snoRNAs) that specifically localise to the Cajal body, a nuclear organelle involved in the biogenesis of small nuclear ribonucleoproteins. ScaRNAs guide the modification of RNA polymerase II transcribed spliceosomal RNAs U1, U2, U4, U5 and U12.

<span class="mw-page-title-main">Small nuclear ribonucleoprotein D1</span> Protein-coding gene in the species Homo sapiens

Small nuclear ribonucleoprotein Sm D1 is a protein that in humans is encoded by the SNRPD1 gene.

<span class="mw-page-title-main">SNRPB</span> Protein-coding gene in the species Homo sapiens

Small nuclear ribonucleoprotein-associated proteins B and B' is a protein that in humans is encoded by the SNRPB gene.

<span class="mw-page-title-main">Small nuclear ribonucleoprotein D2</span> Protein-coding gene in the species Homo sapiens

Small nuclear ribonucleoprotein Sm D2 is a protein that in humans is encoded by the SNRPD2 gene. It belongs to the small nuclear ribonucleoprotein core protein family, and is required for pre-mRNA splicing and small nuclear ribonucleoprotein biogenesis. Alternative splicing occurs at this locus and two transcript variants encoding the same protein have been identified.

<span class="mw-page-title-main">SNRPD3</span> Protein-coding gene in the species Homo sapiens

Small nuclear ribonucleoprotein Sm D3 is a protein that in humans is encoded by the SNRPD3 gene.

<span class="mw-page-title-main">Small nuclear ribonucleoprotein polypeptide F</span> Protein-coding gene in the species Homo sapiens

Small nuclear ribonucleoprotein F is a protein that in humans is encoded by the SNRPF gene.

<span class="mw-page-title-main">SNRPG</span> Protein-coding gene in the species Homo sapiens

Small nuclear ribonucleoprotein G is a protein that in humans is encoded by the SNRPG gene.

<span class="mw-page-title-main">Kiyoshi Nagai</span> Japanese structural biologist (1949–2019)

Kiyoshi Nagai was a Japanese structural biologist at the MRC Laboratory of Molecular Biology Cambridge, UK. He was known for his work on the mechanism of RNA splicing and structures of the spliceosome.

References

  1. 1 2 Schümperli, D.; R. S. Pillai (2004-10-01). "The special Sm core structure of the U7 snRNP: far-reaching significance of a small nuclear ribonucleoprotein" (PDF). Cellular and Molecular Life Sciences. 61 (19–20): 2560–2570. doi:10.1007/s00018-004-4190-0. ISSN   1420-682X. PMID   15526162. S2CID   5780814.
  2. ↑ Lerner MR, Steitz JA (November 1979). "Antibodies to small nuclear RNAs complexed with proteins are produced by patients with systemic lupus erythematosus". Proc. Natl. Acad. Sci. U.S.A. 76 (11): 5495–9. Bibcode:1979PNAS...76.5495R. doi: 10.1073/pnas.76.11.5495 . PMC   411675 . PMID   316537.
  3. ↑ Lerner MR, Boyle JA, Mount SM, Wolin SL, Steitz JA (January 1980). "Are snRNPs involved in splicing?". Nature. 283 (5743): 220–4. Bibcode:1980Natur.283..220L. doi:10.1038/283220a0. PMID   7350545. S2CID   4266714.
  4. ↑ Weaver, Robert F. (2005). Molecular Biology, p.432-448. McGraw-Hill, New York, NY. ISBN   0-07-284611-9.
  5. ↑ Montzka KA, Steitz JA (1988). "Additional low-abundance human small nuclear ribonucleoproteins: U11, U12, etc". Proc Natl Acad Sci USA. 85 (23): 8885–8889. Bibcode:1988PNAS...85.8885M. doi: 10.1073/pnas.85.23.8885 . PMC   282611 . PMID   2973606.
  6. ↑ Kiss T (December 2004). "Biogenesis of small nuclear RNPs". J. Cell Sci. 117 (Pt 25): 5949–51. doi:10.1242/jcs.01487. PMID   15564372. S2CID   10316639.
  7. ↑ Meister G, Eggert C, Bühler D, Brahms H, Kambach C, Fischer U (December 2001). "Methylation of Sm proteins by a complex containing PRMT5 and the putative U snRNP assembly factor pICln". Curr. Biol. 11 (24): 1990–4. Bibcode:2001CBio...11.1990M. doi:10.1016/S0960-9822(01)00592-9. hdl: 11858/00-001M-0000-0012-F501-7 . PMID   11747828. S2CID   14742376.
  8. ↑ Paushkin S, Gubitz AK, Massenet S, Dreyfuss G (June 2002). "The SMN complex, an assemblyosome of ribonucleoproteins". Curr. Opin. Cell Biol. 14 (3): 305–12. doi:10.1016/S0955-0674(02)00332-0. PMID   12067652.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ↑ Yong J, Wan L, Dreyfuss G (May 2004). "Why do cells need an assembly machine for RNA-protein complexes?". Trends Cell Biol. 14 (5): 226–32. doi:10.1016/j.tcb.2004.03.010. PMID   15130578.
  10. ↑ Coady, Tristan H.; Lorson, Christian L. (2011). "SMN in spinal muscular atrophy and snRNP biogenesis". Wiley Interdisciplinary Reviews: RNA. 2 (4): 546–564. doi:10.1002/wrna.76. PMID   21957043. S2CID   19534375.
  11. ↑ Stark, Holger; Reinhard Lührmann (2006). "Cryo-Electron Microscopy of Spliceosomal Components". Annual Review of Biophysics and Biomolecular Structure. 35 (1): 435–457. doi:10.1146/annurev.biophys.35.040405.101953. PMID   16689644.
  12. ↑ Pomeranz Krummel, Daniel A.; Chris Oubridge; Adelaine K. W. Leung; Jade Li; Kiyoshi Nagai (2009-03-26). "Crystal structure of human spliceosomal U1 snRNP at 5.5[thinsp]A resolution". Nature. 458 (7237): 475–480. doi:10.1038/nature07851. ISSN   0028-0836. PMC   2673513 . PMID   19325628.
  13. ↑ Weber, Gert; Simon Trowitzsch; Berthold Kastner; Reinhard Luhrmann; Markus C Wahl (2010-12-15). "Functional organization of the Sm core in the crystal structure of human U1 snRNP". EMBO J. 29 (24): 4172–4184. doi:10.1038/emboj.2010.295. ISSN   0261-4189. PMC   3018796 . PMID   21113136.
  14. ↑ Stark, Holger; Prakash Dube; Reinhard Luhrmann; Berthold Kastner (2001-01-25). "Arrangement of RNA and proteins in the spliceosomal U1 small nuclear ribonucleoprotein particle". Nature. 409 (6819): 539–542. Bibcode:2001Natur.409..539S. doi:10.1038/35054102. ISSN   0028-0836. PMID   11206553. S2CID   4421636.
  15. ↑ Golas, Monika M.; Bjoern Sander; Cindy L. Will; Reinhard Lührmann; Holger Stark (2005-03-18). "Major Conformational Change in the Complex SF3b upon Integration into the Spliceosomal U11/U12 di-snRNP as Revealed by Electron Cryomicroscopy". Molecular Cell. 17 (6): 869–883. doi:10.1016/j.molcel.2005.02.016. hdl: 11858/00-001M-0000-0010-93F4-1 . ISSN   1097-2765. PMID   15780942.
  16. ↑ Sander, Bjoern; Monika M. Golas; Evgeny M. Makarov; Hero Brahms; Berthold Kastner; Reinhard Lührmann; Holger Stark (2006-10-20). "Organization of Core Spliceosomal Components U5 snRNA Loop I and U4/U6 Di-snRNP within U4/U6.U5 Tri-snRNP as Revealed by Electron Cryomicroscopy". Molecular Cell. 24 (2): 267–278. doi:10.1016/j.molcel.2006.08.021. hdl: 11858/00-001M-0000-0010-93DC-C . ISSN   1097-2765. PMID   17052460.
  17. ↑ Will, Cindy L.; Reinhard Lührmann (2011-07-01). "Spliceosome Structure and Function". Cold Spring Harbor Perspectives in Biology. 3 (7): a003707. doi:10.1101/cshperspect.a003707. PMC   3119917 . PMID   21441581.
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