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arrangement that ensures the formation and stability of their interaction
( Fig. 6.2 ). From this evolutionarily perspective, it is not surprising that a
large fraction of spliceosomal proteins directly associate with an snRNA,
often assisting it in its function. 5,85 However, many spliceosomal proteins
are involved in performing regulatory functions not required in the context
of a self-splicing intron and are likely to be more recent additions to the
spliceosomal protein complement.
As mentioned above, it is thought that the last common ancestor of
eukaryotes had a highly evolved, fully functional spliceosome which resem-
bled those found in modern eukaryotes. 1,2 Although this spliceosome likely
contained significantly fewer components compared to even the smallest of
modern spliceosomes, data indicate that most of the key components were
present in the earliest versions of the spliceosomes. 1-4 Indeed, a subset of the
spliceosomal proteome that includes proteins associated with the catalytic
core show a significant level of conservation among different eukaryotic spe-
cies, with a number of spliceosomal proteins being among the most con-
served cellular proteins. 85,86
As mentioned above, many well-characterized ribozymes are associated
with proteins in vivo which improve their catalytic activity by several known
mechanisms. 83 These include stabilizing the functional structure of the RNAs,
assisting in binding and positioning of the substrates, and assisting in binding of
functionally important metal ions. However, direct participation in catalysis
has so far not been observed for any of the ribozyme-associated proteins stud-
ied. 83,87 If one assumes that the spliceosome is an RNA enzyme, the
spliceosomal snRNAs are unusual ribozymes in many respects. Perhaps most
importantly, they are unusually small for a ribozyme catalyzing phosphodiester
bond cleavage via the activation of a nonadjacent nucleophile. Other natural
ribozymes catalyzing such reactions, namely group I and II introns and RNase
P, are at least twofold longer than the combined length of human U6 and U2
snRNAs. These ribozymes are also much larger than the nucleolytic
ribozymes that activate an adjacent 2 0 -hydroxyl nucleophile for pho-
sphodiester bond cleavage. 24,88,89 The larger size is thought to allow these
ribozymes to fold into complex structures stabilized by multiple tertiary inter-
actions, which in turn enable them to create sophisticated active sites capable
of accurately positioning the cleavage site, the active site metal ions, and the
remote nucleophile for in-line nucleophilic attack. It is conceivable that U6
and U2 snRNAs, due to their short length, at best form an inefficient splicing
ribozyme that requires other spliceosomal factors for stable positioning of the
active site elements and the reacting groups.
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