| Structural highlights
Function
PPIH_HUMAN PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides. Participates in pre-mRNA splicing. May play a role in the assembly of the U4/U5/U6 tri-snRNP complex. May act as a chaperone.[1] [2] [3]
Publication Abstract from PubMed
Early spliceosome assembly can occur through an intron-defined pathway, whereby U1 and U2 small nuclear ribonucleoprotein particles (snRNPs) assemble across the intron(1). Alternatively, it can occur through an exon-defined pathway(2-5), whereby U2 binds the branch site located upstream of the defined exon and U1 snRNP interacts with the 5' splice site located directly downstream of it. The U4/U6.U5 tri-snRNP subsequently binds to produce a cross-intron (CI) or cross-exon (CE) pre-B complex, which is then converted to the spliceosomal B complex(6,7). Exon definition promotes the splicing of upstream introns(2,8,9) and plays a key part in alternative splicing regulation(10-16). However, the three-dimensional structure of exon-defined spliceosomal complexes and the molecular mechanism of the conversion from a CE-organized to a CI-organized spliceosome, a pre-requisite for splicing catalysis, remain poorly understood. Here cryo-electron microscopy analyses of human CE pre-B complex and B-like complexes reveal extensive structural similarities with their CI counterparts. The results indicate that the CE and CI spliceosome assembly pathways converge already at the pre-B stage. Add-back experiments using purified CE pre-B complexes, coupled with cryo-electron microscopy, elucidate the order of the extensive remodelling events that accompany the formation of B complexes and B-like complexes. The molecular triggers and roles of B-specific proteins in these rearrangements are also identified. We show that CE pre-B complexes can productively bind in trans to a U1 snRNP-bound 5' splice site. Together, our studies provide new mechanistic insights into the CE to CI switch during spliceosome assembly and its effect on pre-mRNA splice site pairing at this stage.
Structural insights into the cross-exon to cross-intron spliceosome switch.,Zhang Z, Kumar V, Dybkov O, Will CL, Zhong J, Ludwig SEJ, Urlaub H, Kastner B, Stark H, Luhrmann R Nature. 2024 May 22. doi: 10.1038/s41586-024-07458-1. PMID:38778104[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Teigelkamp S, Achsel T, Mundt C, Gothel SF, Cronshagen U, Lane WS, Marahiel M, Luhrmann R. The 20kD protein of human [U4/U6.U5] tri-snRNPs is a novel cyclophilin that forms a complex with the U4/U6-specific 60kD and 90kD proteins. RNA. 1998 Feb;4(2):127-41. PMID:9570313
- ↑ Horowitz DS, Lee EJ, Mabon SA, Misteli T. A cyclophilin functions in pre-mRNA splicing. EMBO J. 2002 Feb 1;21(3):470-80. PMID:11823439
- ↑ Reidt U, Wahl MC, Fasshauer D, Horowitz DS, Luhrmann R, Ficner R. Crystal structure of a complex between human spliceosomal cyclophilin H and a U4/U6 snRNP-60K peptide. J Mol Biol. 2003 Aug 1;331(1):45-56. PMID:12875835
- ↑ Zhang Z, Kumar V, Dybkov O, Will CL, Zhong J, Ludwig SEJ, Urlaub H, Kastner B, Stark H, Lührmann R. Structural insights into the cross-exon to cross-intron spliceosome switch. Nature. 2024 May 22. PMID:38778104 doi:10.1038/s41586-024-07458-1
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