The Role of snRNAs in Spliceosomal Catalysis - Progress in Molecular Biology and Translational Science - page 216

complex set of interactions to form the Prp19/CDC5 complex in human
and the NineTeen Complex (NTC) in yeast. 117,118 The NTC is required
for stable association of U5 and U6 with the exonic sequences and the 5 0
splice site in the last assembly steps prior to catalytic activation of the
spliceosome. 117,119,120 It has been shown that NTC is involved in mediating
a conformational change in U6 that involves remodeling of its interaction
with the 5 0 splice site. 117,121 In human, Prp19 is also found together with
CDC5 in a larger complex containing 30 proteins, and it is likely to play

a role in the second step of splicing. 122 Recently, it has been shown that
Cwc21, a member of the NTC, binds directly to both Prp8 and Snu114
and may thus mediate interaction of the NTC with the U5 snRNP. 123
Taken together, the existing data suggest that NTC is involved in stabilizing
a number of RNA-RNA interactions in the latest steps before formation of
the catalytically competent spliceosomes. 112,124 Therefore, a complex net-
work of protein-protein and RNA-protein interactions contribute to the
formation of the U6/U2 complex during the catalytic activation of the
spliceosome and subsequent catalytic steps. Although detailed information
regarding their exact roles in the formation of the active site is lacking, it
is likely that they contribute to the formation and stabilization of function-
ally critical interactions between U6 and U2 snRNAs and between snRNAs
and pre-mRNA.

11. CONCLUDING REMARKS
The spliceosome is ultimately an enzyme that acts on an RNA sub-
strate. It is also a RNP complex that has evolved around a core of five short
RNAs that are most likely descendants of an ancient catalytic RNA. While a
large body of evidence suggests that the spliceosomal snRNAs form all or at
least a major part of the spliceosomal active site, perhaps the most pivotal
question remaining is the extent to which proteins modulate or participate
in splicing catalysis. As expected from an RNP enzyme with an RNA sub-
strate, a significant fraction of spliceosomal proteins closely associate with
snRNAs and seem to function by remodeling RNA-RNA interactions.
Although the availability of a high-resolution structure of the spliceosome
would provide fundamental insights into this and many other questions
remaining in the splicing field, it is unfortunately unlikely that such struc-
tural information will be available in the near future. Although the existence
of high-resolution structural data for other natural ribozymes has helped
guide the direction of scientific inquiry, in most cases it has not been