snRNP

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]

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
See also: LSm § Gemin6 and Gemin7

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).

References
  1. 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.
  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. 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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