Prp24: Difference between revisions

Prp24 is a U6 snNRP protein that functions in the annealing of the U4 and U6 snRNPs during the assembly of the spliceosome.  This protein was first identified in a genetic screen as mutated gene that caused an accumulation of pre-mRNA <ref name="Vij">PMID:2676722</ref>.  It's first functional role was suggested after several mutant forms of the protein were found to suppress a cold sensitive growth defect caused by mutations in the U4 snRNA <ref name="Shannon">PMID:1827420</ref>.  It is thought that Prp24 helps to stabilize the U6 snRNA and hold it in a conformation that promotes base pairing interactions with the U4 snRNA to form the stem I and stem II structures of the U4/U6 di-snRNP <ref name="Vidaver">PMID:10545453</ref>.  Prp24 departs from the U4/U6 complex before the formation of the U4/U6.U5 tri-snRNP, but it has been suggested that Prp24 may also play a role in the dissociation of U4 from U6 during the base pairing of U6 with U2 and the 5' splice site <ref name="Vaidya">DOI:10.1007/BF02966594</ref>.  This additional role for Prp24, however, has not been sufficiently supported experimentally.       

The Lsm proteins are a set of seven proteins found in the U6 snRNP that form a ring around the 3' end of U6 <ref name="Karaduman2008"/>.  An interaction between Prp24 and the Lsm proteins was suggested upon identification of the Lsms and the fact that formation of U4/U6 by Prp24 was less efficient in deproteinized solutions of U4 and U6 snRNAs <ref name="Raghunathan"/>, as well as the identification of a genetic interaction between the genes for Prp24 and Lsm4 <ref name="Mayes">DOI:10.1093/emboj/18.15.4321</ref>.  This proposed interaction was further supported by UV cross-linking experiments in which both Prp24 and Lsm4 were immunoprecipitated with U6 after cross-linking (reference Vidal et al. 1999).  It has also been shown that both Prp24 and Lsm4, as well as the other Lsm proteins, require the 3' end of U6 in order to interact with the snRNA (Vidal et al. 1999), suggesting that this may be the region where the proteins interact.  Genome-wide protein interaction screens showed that Prp24 interacts additionally with Lsm 2, 5, 6, 7 and 8, and that overexpression of either Prp24 or Lsm4 can complement or intensify the effects of a defect in the other protein (Fromont-Racine et al. 2000), further supporting an interaction between the Lsm proteins and Prp24.

Evidence for a direct interaction of Prp24 and the Lsm proteins comes from a study in which the conserved residues in the C-terminal domain of Prp24 were deleted, resulting in lowered levels of U4/U6 and very literal interaction with the Lsm proteins as compared to wild-type Prp24, indicating that Prp24 interacts directly with the Lsm proteins and the C-terminal domain is necessary for this interaction (Rader and Guthrie 2002).  Another indication of interaction between Prp24 and the Lsm proteins stems from a study showing that Lsm6 and Lsm7 are necessary in cells that require the recycling of the U4/U6 complex for splicing and that the presence of these two proteins increases the efficiency of annealing of U4 and U6 (Verdone et al. 2004).  This suggests that Lsm6 and 7 are involved in a necessary interaction with Prp24 in the formation of U4/U6 di-snRNP.   

More recently, a study has suggested that Prp24 interacts specifically with all the Lsm proteins involved in the U6 snRNP, and that the proteins act together as molecular chaperones to restructure and stabilize the 3' stem of U6 for base-pairing with U4 in stem II of U4/U6(Karaduman et al. 2006).  Further support for specific interactions of Prp24 with the Lsm proteins comes from an electron microscopy study that showed Prp24 at specific differences from the subunits of the Lsm ring, suggesting that it interacts from a specified position within the U6 snRNP (Karaduman et al. 2006).

Several additional roles for Prp24 have been suggested in spliceosome assembly/disassembly, although nothing has been sufficiently supported.  A genetic interaction in which Prp24 mutation suppressed a Prp21 (a component of the U2 snRNP) mutation suggested that the two proteins may interact during the base pairing of U2 and U6 at the 5' splice site (reference Vaidya et al. 1996).  However, further investigation failed to produce evidence of an interaction between the two proteins, but the authors maintained that a transient interaction between Prp24 and Prp21 may exist in an intermediate form of the assembling spliceosome (reference Vaidya and Vijayraghavan 1998).  It has also been suggested that Prp24 may serve in the destabilization of the U4/U6 complex to allow base pairing of U5 (reference) or in destabilization of U6 from U2 upon completion of splicing to release free U6 snRNP, but again, there have been no studies showing support for these roles of the protein (Vidaver et al. 1999).