Met/Val129 polymorphism of the full-length human prion protein dictates distinct pathways of amyloid formation

Pauly, T.A.; Bolakhrif, Najoua; Kaiser, Jesko; Nagel-Steger, Luitgard; Gremer, Lothar; Gohlke, Holger; Willbold, Dieter

doi:10.1016/j.jbc.2022.102430

Cited by 5 publications

(1 citation statement)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The AMBER22 package of molecular simulations software (92,93) was used in combination with the ff19SB force field for protein atoms (94) and the RNA OL3 force field (95) for RNA atoms. MD simulations were performed as described earlier (96). In short, a combination of steepest descent and conjugate gradient minimization was performed while lowering positional restraints on solute atoms from 25 kcal mol -1 Å -2 to zero, followed by a stepwise heating procedure and lowering harmonic restraints on solute atoms from 1 kcal mol -1 Å -2 to zero.…”

Section: Molecular Dynamics Simulationsmentioning

confidence: 99%

Long-read transcriptome sequencing of CLL and MDS patients uncovers molecular effects ofSF3B1mutations

Pacholewska,

Lienhard,

Brüggemann

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

BackgroundMutations in splicing factor 3B subunit 1 (SF3B1) frequently occur in patients with chronic lymphocytic leukemia (CLL) and myelodysplastic syndromes (MDS). These mutations have a different effect on the disease prognosis with beneficial effect in MDS and worse prognosis in CLL patients. A full-length transcriptome approach can expand our knowledge onSF3B1mutation effects on RNA splicing and its contribution to patient survival and treatment options.ResultsWe applied long-read transcriptome sequencing to 44 MDS and CLL patients with and withoutSF3B1mutations and found > 60% of novel isoforms. Splicing alterations were largely shared between cancer types and specifically affected the usage of introns and 3’ splice sites. Our data highlighted a constrained window at canonical 3’ splice sites in which dynamic splice site switches occurred inSF3B1-mutated patients. Using transcriptome-wide RNA binding maps and molecular dynamics simulations, we showed multimodal SF3B1 binding at 3’ splice sites and predicted reduced RNA binding at the second binding pocket of SF3B1K700E.ConclusionsOur work presents the hitherto most complete long-read transcriptome sequencing study in CLL and MDS and provides a resource to study aberrant splicing in cancer. Moreover, we showed that different disease prognosis results most likely from the different cell types expanded during cancerogenesis rather than different mechanism of action of the mutatedSF3B1. These results have important implications for understanding the role ofSF3B1mutations in hematological malignancies and other related diseases.HighlightsLong-read transcriptome sequencing data enables the identification of > 60% of novel isoforms in the transcriptomes of CLL and MDS patients and isogenic cell lines.SF3B1mutations trigger common splicing alterations uponSF3B1mutations across patient cohorts, most frequently decreased intron retention and increased alternative 3’ splice site usage.Mutation effect depends on alternative 3’ splice site and branch point positioning that coincide with bimodal SF3B1 binding at these sitesMolecular dynamics simulations predict reduced binding of SF3B1K700Eto mRNA at the second binding pocket harboring the polypyrimidine tract.

show abstract