Ask about this productRelated genes to: SF3B1 Blocking Peptide
- Gene:
- SF3B1 NIH gene
- Name:
- splicing factor 3b subunit 1
- Previous symbol:
- -
- Synonyms:
- SAP155, SF3b155, PRPF10, Prp10, Hsh155
- Chromosome:
- 2q33.1
- Locus Type:
- gene with protein product
- Date approved:
- 2000-02-29
- Date modifiied:
- 2019-04-23
- Gene:
- SF3B6 NIH gene
- Name:
- splicing factor 3b subunit 6
- Previous symbol:
- -
- Synonyms:
- P14, SF3B14a, Ht006, CGI-110, SAP14a
- Chromosome:
- 2p23.3
- Locus Type:
- gene with protein product
- Date approved:
- 2014-02-14
- Date modifiied:
- 2016-10-05
Related products to: SF3B1 Blocking Peptide
Related articles to: SF3B1 Blocking Peptide
- Formation of the activated human spliceosome (B) involves major structural rearrangements, leading to the catalytically active U2/U6 RNA core. This process involves at least two intermediates, pre-B and pre-B, and is regulated by CDK11-mediated phosphorylation of the U2 snRNP protein SF3B1. However, the mechanisms of this essential step are poorly understood. Here we present the cryo-EM structure of a spliceosome stalled - by the CDK11 inhibitor OTS964 - in a previously undescribed early-activated state, termed pre-B, shortly after dissociation of U4 snRNP. In pre-B, the U2-SF3B6 protein is retained in a C-terminal region of the super-helical U2-SF3B1 HEAT domain (SF3B1) that clamps the U2/branch-site helix. In contrast, in pre-B, SF3B6 is repositioned to SF3B1's N-terminal HEAT repeats, thereby preventing a steric clash of SF3B6 with PRP8 during the pre-B-to-pre-B transition. We infer that the CDK11-mediated phosphorylation of SF3B1 drives the relocation of SF3B6, gating progression to B formation. In pre-B, we also located the RNA helicase DHX15 at the N-terminal region of SF3B1, assisted by the SR140/SPF45/CHERP/SUGP1 protein complex. These results suggest the involvement of DHX15 in kinase-mediated proofreading of the early-activated spliceosome, by competing with CDK11's phosphorylation of SF3B1, and thus with relocation of SF3B6 at SF3B1. - Source: PubMed
Publication date: 2026/07/03
Zhang ZhenweiKumar VinayPanta SumeruZhong JiayunDybkov OlexandrDong HaohaoKastner BertholdUrlaub HenningStark HolgerLührmann Reinhard - The SF3B splicing complex is composed of SF3B1-6 and PHF5A. We report a developmental disorder caused by de novo variants in PHF5A. - Source: PubMed
Publication date: 2023/07/06
Harms Frederike LDingemans Alexander J MHempel MajaPfundt RolphBierhals TatjanaCasar ChristianMüller ChristianNiermeijer Jikke-Mien FFischer JanJahn ArneHübner ChristophMajore SilviaAgolini EmanueleNovelli Antoniovan der Smagt JasperErnst Robertvan Binsbergen EllenMancini Grazia M Svan Slegtenhorst MarjonBarakat Tahsin StefanWakeling Emma LKamath ArveenDownie LilianPais LynnWhite Susan Mde Vries Bert B AKutsche Kerstin - During spliceosome assembly, the 3' splice site is recognized by sequential U2AF2 complexes, first with Splicing Factor 1 (SF1) and second by the SF3B1 subunit of the U2 small nuclear ribonuclear protein particle. The U2AF2-SF1 interface is well characterized, comprising a U2AF homology motif (UHM) of U2AF2 bound to a U2AF ligand motif (ULM) of SF1. However, the structure of the U2AF2-SF3B1 interface and its importance for pre-mRNA splicing are unknown. To address this knowledge gap, we determined the crystal structure of the U2AF2 UHM bound to a SF3B1 ULM site at 1.8-Å resolution. We discovered a distinctive trajectory of the SF3B1 ULM across the U2AF2 UHM surface, which differs from prior UHM/ULM structures and is expected to modulate the orientations of the full-length proteins. We established that the binding affinity of the U2AF2 UHM for the cocrystallized SF3B1 ULM rivals that of a nearly full-length U2AF2 protein for an N-terminal SF3B1 region. An additional SF3B6 subunit had no detectable effect on the U2AF2-SF3B1 binding affinities. We further showed that key residues at the U2AF2 UHM-SF3B1 ULM interface contribute to coimmunoprecipitation of the splicing factors. Moreover, disrupting the U2AF2-SF3B1 interface changed splicing of representative human transcripts. From analysis of genome-wide data, we found that many of the splice sites coregulated by U2AF2 and SF3B1 differ from those coregulated by U2AF2 and SF1. Taken together, these findings support distinct structural and functional roles for the U2AF2-SF1 and U2AF2-SF3B1 complexes during the pre-mRNA splicing process. - Source: PubMed
Publication date: 2022/07/01
Galardi Justin WBela Victoria NJeffery NazishHe XueyangGlasser EliezraLoerch SarahJenkins Jermaine LPulvino Mary JBoutz Paul LKielkopf Clara L - Multi-protein assemblies are complex molecular systems that perform highly sophisticated biochemical functions in an orchestrated manner. They are subject to changes that are governed by the evolution of individual components. We performed a comparative analysis of the ancient and functionally conserved spliceosomal SF3b complex, to recognize molecular signatures that contribute to sequence divergence and functional specializations. For this, we recognized homologous sequences of individual SF3b proteins distributed across 10 supergroups of eukaryotes and identified all seven protein components of the complex in 578 eukaryotic species. Using sequence and structural analysis, we establish that proteins occurring on the surface of the SF3b complex harbor more sequence variation than the proteins that lie in the core. Further, we show through protein interface conservation patterns that the extent of conservation varies considerably between interacting partners. When we analyze phylogenetic distributions of individual components of the complex, we find that protein partners that are known to form independent subcomplexes are observed to share similar profiles, reaffirming the link between differential conservation of interface regions and their inter-dependence. When we extend our analysis to individual protein components of the complex, we find taxa-specific variability in molecular signatures of the proteins. These trends are discussed in the context of proline-rich motifs of SF3b4, functional and drug binding sites of SF3b1. Further, we report key protein-protein interactions between SF3b1 and SF3b6 whose presence is observed to be lineage-specific across eukaryotes. Together, our studies show the association of protein location within the complex and subcomplex formation patterns with the sequence conservation of SF3b proteins. In addition, our study underscores evolutionarily flexible elements that appear to confer adaptive features in individual components of the multi-protein SF3b complexes and may contribute to its functional adaptability. - Source: PubMed
Publication date: 2022/01/10
Yazhini ArangasamySrinivasan NarayanaswamySandhya Sankaran - The evolution of homologous and functionally equivalent multiprotein assemblies is intriguing considering sequence divergence of constituent proteins. Here, we studied the implications of protein sequence divergence on the structure, dynamics and function of homologous yeast and human SF3b spliceosomal subcomplexes. Human and yeast SF3b comprise of 7 and 6 proteins respectively, with all yeast proteins homologous to their human counterparts at moderate sequence identity. SF3b6, an additional component in the human SF3b, interacts with the N-terminal extension of SF3b1 while the yeast homologue Hsh155 lacks the equivalent region. Through detailed homology studies, we show that SF3b6 is absent not only in yeast but in multiple lineages of eukaryotes implying that it is critical in specific organisms. We probed for the potential role of SF3b6 in the spliceosome assembled form through structural and flexibility analyses. By analysing normal modes derived from anisotropic network models of SF3b1, we demonstrate that when SF3b1 is bound to SF3b6, similarities in the magnitude of residue motions (0.86) and inter-residue correlated motions (0.94) with Hsh155 are significantly higher than when SF3b1 is considered in isolation (0.21 and 0.89 respectively). We observed that SF3b6 promotes functionally relevant 'open-to-close' transition in SF3b1 by enhancing concerted residue motions. Such motions are found to occur in the Hsh155 without SF3b6. The presence of SF3b6 influences motions of 16 residues that interact with U2 snRNA/branchpoint duplex and supports the participation of its interface residues in long-range communication in the SF3b1. These results advocate that SF3b6 potentially acts as an allosteric regulator of SF3b1 for BPS selection and might play a role in alternative splicing. Furthermore, we observe variability in the relative orientation of SF3b4 and in the local structure of three β-propeller domains of SF3b3 with reference to their yeast counterparts. Such differences influence the inter-protein interactions of SF3b between these two organisms. Together, our findings highlight features of SF3b evolution and suggests that the human SF3b may have evolved sophisticated mechanisms to fine tune its molecular function. - Source: PubMed
Publication date: 2021/06/15
Yazhini ArangasamySandhya SankaranSrinivasan Narayanaswamy