snRNPs, or small nuclear ribonucleic proteins, 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 to process the
3′ stem-loop of histone pre-mRNA. 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. 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.
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. Additionally, U7 snRNP is made U7 small
nuclear RNA and associated proteins and is involved in the processing of the 3′
stem-loop of histone pre-mRNA. Biogenesis
Small nuclear ribonucleoproteins assemble in a tightly orchestrated and
regulated process that involves both the cell nucleus and cytoplasm.
= 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 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 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 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 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 quickly interact with the SMN
protein and Gemins 2-8 forming the 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. After assembly of the Sm ring around the snRNA, the 5' terminal
nucleoside is hyper-methylated to 2,2,7-trimethylguanosine and the other
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. 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 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. Structures, function and organization
Several human and yeast snRNP structures were determined by the cryo-electron
microscopy and successive single particle analysis. Recently, the human
U1 snRNP core structure was determined by X-ray crystallography, followed by a
structure of the U4 core snRNP, 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 as
well as a structure of its 3'-Nucleotides bound to the special
Lsm2-8 protein ring. The PDB codes for the respective structures are mentioned
in parenthesis. The structures determined by single particle electron
microscopy analysis are: human U1 snRNP , human U11/U12 di-snRNP human U5
snRNP, U4/U6 di-snRNP, U4/U6∙U5 tri-snRNP . The further progress
determining the structures and functions of snRNPs and spliceosomes continues.
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.
References External links
Joan Steitz's short talk: "SNURPs and Serendipity"
snRNP at the US National Library of Medicine Medical Subject Headings