Rice D53 repression motif links two sites of TPL corepressors to mediate TPL oligomerization and nucleosome association.

PCI domain proteins play important roles in post-transcriptional gene regulation. In the TREX-2 complex, PCI domain-containing Sac3 and Thp1 proteins and accessory Sem1 protein form a ternary complex required for mRNA nuclear export. In contrast, structurally related Thp3–Csn12–Sem1 complex mediates pre-mRNA splicing. In this study, we determined the structure of yeast Thp3^186–470–Csn12–Sem1 ternary complex at 2.9 Å resolution. Both Thp3 and Csn12 structures have a typical PCI structural fold, characterized by a stack of α-helices capped by a C-terminal winged-helix (WH) domain. The overall structure of Thp3^186–470–Csn12–Sem1 complex has an inverted V-shape with Thp3 and Csn12 forming the two sides. A fishhook-shaped Sem1 makes extensive contacts on Csn12 to stabilize its conformation. The overall structure of Thp3^186–470–Csn12–Sem1 complex resembles the previously reported Sac3–Thp1–Sem1 complex, but also has significant structural differences. The C-terminal WH domains of Thp3 and Csn12 form a continuous surface to bind different forms of nucleic acids with micromolar affinity. Mutation of the basic residues in the WH domains of Thp3 and Csn12 affects nucleic acid binding in vitro and mRNA splicing in vivo. The Thp3–Csn12–Sem1 structure provides a foundation for further exploring the structural elements required for its specific recruitment to spliceosome for pre-mRNA splicing.

Background: Gliomas are highly aggressive, life-threatening tumors with poor prognosis, and remain a leading cause of mortality among brain cancers. Although the role of mitochondrial proteins in cancer has garnered increasing attention, their specific functions in the nervous system, particularly in gliomas, remain poorly understood.Methods: We integrated single-cell RNA sequencing with cellular assays and flow cytometry to investigate the molecular characteristics and cellular interactions within glioblastoma subpopulations during tumor progression.Results: Single-cell RNA sequencing revealed several differentially expressed genes (DEGs) within glioblastoma subpopulations. Trajectory analysis identified CHCHD2P9 as a pivotal marker for the terminal subpopulation. Moreover, elevated expression of CHCHD2P9 was found to correlate with poorer clinical outcomes. Subsequent cellular experiments further explored the underlying mechanisms driving these observations.Conclusions: CHCHD2P9 is significantly overexpressed in glioma patients, and its differential expression plays a crucial role in regulating glioma cell proliferation and migration. A CHCHD2P9-based risk model holds promise as both a prognostic biomarker and a potential therapeutic target, providing novel insights into the pathogenesis of gliomas and opening avenues for personalized treatment strategies.

Agkisacucetin, a snake C-type lectin-like protein isolated from the venom of Deinagkistrodon acutus (formerly Agkistrodon acutus), is a novel antithrombotic drug candidate in phase 2 clinical trials. Agkisacucetin specifically recognizes the platelet surface receptor glycoprotein Ib α chain (GPIbα) to block GPIb and von Willebrand factor (VWF). In this study, we solved the crystal structure of the GPIbα N-terminal domain (residues 1-305) in complex with agkisacucetin to understand their molecular recognition mechanism. The crystal structure showed that agkisacucetin primarily contacts GPIbα at the C-terminal part of the conserved leucine-rich repeat (LRR) domain (LRR-6 to LRR-8) and the previously described “β-switch” region through the β chain. In addition, we found that agkisacucetin α chain contacts part of the GPIbα C-terminal peptide after the LRR domain through complementary charge interactions. This C-terminal peptide plays a key role in GPIbα and thrombin recognition. Therefore, our structure revealed that agkisacucetin can sterically block the interaction between the GPIb receptor and VWF and thrombin proteins to inhibit platelet function. Our structural work provides key molecular insights into how an antithrombotic drug candidate recognizes the GPIb receptor to modulate platelet function to inhibit thrombosis.