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.

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.[1][2] 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 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.[3]

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.[4]

Biogenesis

Small nuclear ribonucleoproteins (snRNPs) assemble in a tightly orchestrated and regulated process that involves both the cell nucleus and cytoplasm.[5]

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 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 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.[6] 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 Neurons) protein and other proteins (Gemins 2-8) forming the large SMN complex.[7][8] 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. Nothing is known about this process.

Defects in snRNP biogenesis as a cause of Spinal muscular atrophy

Defects in the SMN gene are associated with premature death of spinal motor neurons, and results in Spinal muscular atrophy (SMA).[9] 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.

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. ^ 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. doi:10.1073/pnas.76.11.5495. PMID 316537.
2. ^ Lerner MR, Boyle JA, Mount SM, Wolin SL, Steitz JA (January 1980). "Are snRNPs involved in splicing?". Nature 283 (5743): 220–4. doi:10.1038/283220a0. PMID 7350545.
3. ^ Weaver, Robert F. (2005). Molecular Biology, p.432-448. McGraw-Hill, New York, NY. ISBN 0072846119.
4. ^ Montzka, KA; Steitz JA (1988). "Additional low-abundance human small nuclear ribonucleoproteins: U11, U12, etc". Proc Natl Acad Sci USA 85: 8885–8889. doi:10.1073/pnas.85.23.8885. PMID 2973606.
5. ^ Kiss T (December 2004). "Biogenesis of small nuclear RNPs". J. Cell. Sci. 117 (Pt 25): 5949–51. doi:10.1242/jcs.01487. PMID 15564372. http://jcs.biologists.org/cgi/content/full/117/25/5949.
6. ^ 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. PMID 11747828. http://linkinghub.elsevier.com/retrieve/pii/S0960-9822(01)00592-9.
7. ^ 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. http://linkinghub.elsevier.com/retrieve/pii/S0955067402003320.
8. ^ 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. http://linkinghub.elsevier.com/retrieve/pii/S0962892404000844.
9. ^ Selenko P, Sprangers R, Stier G, Bühler D, Fischer U, Sattler M (January 2001). "SMN tudor domain structure and its interaction with the Sm proteins". Nat. Struct. Biol. 8 (1): 27–31. doi:10.1038/8301410.1038/83014 (inactive 2010-03-19). PMID 11135666.

External links

* MeSH snRNP