Progression through the spliceosome cycle requires Prp38p function for U4/U6 snRNA dissociation

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Abstract
The elaborate and energy‐intensive spliceosome assembly pathway belies the seemingly simple chemistry of pre‐mRNA splicing. Prp38p was previously identified as a protein required in vivo and in vitro for the first pre‐mRNA cleavage reaction catalyzed by the spliceosome. Here we show that Prp38p is a unique component of the U4/U6.U5 tri‐small nuclear ribonucleoprotein (snRNP) particle and is necessary for an essential step late in spliceosome maturation. Without Prp38p activity spliceosomes form, but arrest in a catalytically impaired state. Functional spliceosomes shed U4 snRNA before 5′ splice‐site cleavage. In contrast, Prp38p‐defective spliceosomes retain U4 snRNA bound to its U6 snRNA base‐pairing partner. Prp38p is the first tri‐snRNP‐specific protein shown to be dispensable for assembly, but required for conformational changes which lead to catalytic activation of the spliceosome.