8qpa
From Proteopedia
Cryo-EM Structure of Pre-B+5'ssLNG Complex (core part)
Structural highlights
DiseaseU520_HUMAN Retinitis pigmentosa. Retinitis pigmentosa 33 (RP33) [MIM:610359: A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. Note=The disease is caused by mutations affecting the gene represented in this entry.[1] [2] [3] [4] [5] FunctionU520_HUMAN RNA helicase that plays an essential role in pre-mRNA splicing as component of the U5 snRNP and U4/U6-U5 tri-snRNP complexes. Involved in spliceosome assembly, activation and disassembly. Mediates changes in the dynamic network of RNA-RNA interactions in the spliceosome. Catalyzes the ATP-dependent unwinding of U4/U6 RNA duplices, an essential step in the assembly of a catalytically active spliceosome.[6] [7] [8] [9] Publication Abstract from PubMedEarly 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[10] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
Categories: Homo sapiens | Large Structures | Dybkov O | Kastner B | Kumar V | Ludwig S | Luehrmann R | Stark H | Urlaub H | Will CL | Zhang Z | Zhong J
