Reactome | Formation of the Spliceosomal C* complex

Formation of the Spliceosomal C* complex

Stable Identifier

R-HSA-9770141

Type

Reaction [uncertain]

Species

Homo sapiens

Compartment

nucleoplasm

Synonyms

Formation of the Active Spliceosomal C complex (update)

ReviewStatus

5/5

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Formation of the Spliceosomal C* complex

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DHX38 (homolog of yeast Prp16) hydrolyzes ATP to remodel the Spliceosomal C complex to the Spliceosomal C* complex (Ortlepp et al. 1998, Zhou and Reed 1998), which will ligate the exons and produce the intron lariat, yielding the Spliceosomal P (post-catalytic) complex. DHX38 appears to dissociate shortly after remodeling the Spliceosomal C complex (Zhang et al. 2017, Kastner et al. 2019). Catalysis of exon ligation will occur in the same active site as branching occurred. Therefore, the pre-mRNA must be moved relative to the active site. DHX38 binds the pre-mRNA downstream of the intron branch point, displaces YJU2 and CWC25, and rotates the branch helix out of the active site to allow the 3' splice junction to enter (Bertram et al. 2017, Zhang et al. 2017). The branch helix is stabilized after re-positioning by CDC40 (homolog of yeast Prp17) bound to the 5' stem-loop of the U6 snRNA and PRPF8 (homolog of yeast Prp8) of the U5 snRNP (Bertram et al. 2017, Zhang et al. 2017). SLU7 and PRPF18 (homolog of yeast Prp18) are components of the Spliceosomal C* complex and participate in docking the 3' splice site in the active site (Bertram et al. 2017, Zhang et al. 2017). The 3' end of the upstream exon base-pairs with loop I of U5 snRNA and the branch point region of the intron base-pairs with the U2 snRNA and U6 snRNA (Bertram et al. 2017, Zhang et al. 2017). As in yeast (Wilkinson et al. 2017), the 3' splice site may form non-Watson-Crick base pairs with the 5' splice site and branch point of the intron. The 3' splice site may also interact with SLU7 (Bertram et al. 2017, Zhang et al. 2017), PRPF18 (homolog of yeast Prp18), and DHX8 (homolog of yeast Prp22). As in the Bact complex, the catalytic magnesium ions of the active Spliceosomal C complex are coordinated by phosphates of the U6 snRNA (Bertram et al. 2017, Zhang et al. 2017). The components of the Spliceosomal C* complex have been ascertained using proteomic and structural methods (Jurica et al. 2002, Makarov et al. 2002, Rappsilber et al. 2002, Ilagan et al. 2013, Bertram et al. 2017, Zhang et al. 2017, Kastner et al. 2019, also inferred from yeast homologs in Fica et al. 2017). Mutations in DHX38 affect splicing and can cause retinitis pigmentosa (Ajmal et al. 2014, Obuca et al. 2022).

Literature References

PubMed ID	Title	Journal	Year
9701291	The mammalian homologue of Prp16p is overexpressed in a cell line tolerant to Leflunomide, a new immunoregulatory drug effective against rheumatoid arthritis Ortlepp, D, Laggerbauer, B, Müllner, S, Achsel, T, Kirschbaum, B, Lührmann, R	RNA	1998
12176931	Large-scale proteomic analysis of the human spliceosome. Rappsilber, J, Ryder, U, Lamond, AI, Mann, M	Genome Res	2002
11991638	Purification and characterization of native spliceosomes suitable for three-dimensional structural analysis. Jurica, MS, Licklider, LJ, Gygi, SR, Grigorieff, N, Moore, MJ	RNA	2002
35385551	Retinitis pigmentosa-linked mutation in DHX38 modulates its splicing activity Obuća, M, Cvačková, Z, Kubovčiak, J, Kolář, M, Staněk, D	PLoS One	2022
23345524	Rearrangements within human spliceosomes captured after exon ligation Ilagan, JO, Chalkley, RJ, Burlingame, AL, Jurica, MS	RNA	2013
30765414	Structural Insights into Nuclear pre-mRNA Splicing in Higher Eukaryotes Kastner, B, Will, CL, Stark, H, Lührmann, R	Cold Spring Harb Perspect Biol	2019
28502770	An Atomic Structure of the Human Spliceosome Zhang, X, Yan, C, Hang, J, Finci, LI, Lei, J, Shi, Y	Cell	2017
12411573	Small nuclear ribonucleoprotein remodeling during catalytic activation of the spliceosome Makarov, EM, Makarova, OV, Urlaub, H, Gentzel, M, Will, CL, Wilm, M, Lührmann, R	Science	2002
24737827	A missense mutation in the splicing factor gene DHX38 is associated with early-onset retinitis pigmentosa with macular coloboma Ajmal, M, Khan, MI, Neveling, K, Khan, YM, Azam, M, Waheed, NK, Hamel, CP, Ben-Yosef, T, De Baere, E, Koenekoop, RK, Collin, RW, Qamar, R, Cremers, FP	J Med Genet	2014
28076346	Cryo-EM structure of a human spliceosome activated for step 2 of splicing Bertram, K, Agafonov, DE, Liu, WT, Dybkov, O, Will, CL, Hartmuth, K, Urlaub, H, Kastner, B, Stark, H, Lührmann, R	Nature	2017
9524131	Human homologs of yeast prp16 and prp17 reveal conservation of the mechanism for catalytic step II of pre-mRNA splicing Zhou, Z, Reed, R	EMBO J	1998