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Spliceosome biogenesis and recycling remains a largely unexplored area. Two papers now reveal how protein chaperones remodel the 20S U5 snRNP, leading to formation of the U4/U6.U5 tri-snRNP.
Pregnancy loss is common in humans, but maternal genetic factors modulating its incidence are largely unknown. In a meta-analysis of genome-wide association studies, researchers identified a genetic variant that seems to increase risk of pregnancy loss by dysregulating meiotic recombination between homologous chromosomes during egg formation.
The mitochondrial translocase complex TIM23 targets several hundreds of proteins to their location in the mitochondrial matrix or inner membrane. Recent studies provide important structural and mechanistic insights into the actions of the protein-import machinery in mitochondria.
Ferroptosis suppressor protein 1 (FSP1, or AIFM2), an NADPH quinone reductase noted to protect cancer cells from ferroptosis, acts in FAD/NADPH binding and proton transfer. Recent papers assess its evolutionarily conserved sites via mutagenesis and define its inhibition as an off-target mediator of brequinar-mediated ferroptosis sensitization.
OAT1 has a fundamental role in the kidney by facilitating the urinary excretion of various drugs and endogenous metabolites. Two studies now present high-resolution structures of OAT1 using cryo-EM, elucidating its intricate polyspecific transport capabilities and paving the way for structure-based drug research and development.
Cells maintain homeostasis under stress conditions by minimizing damages, maintaining structural integrity and modifying the activity of macromolecules and signaling molecules such as kinases and phosphatases. Though a comprehensive view of how stress-regulated signaling pathways regulate cell survival remains elusive, new work sheds some light.
The targeting and modulation of G-protein-coupled receptors (GPCRs) has immense therapeutic potential. A study in Nature now reports on the successful targeting of intracellular allosteric sites that effectively bias GPCR signaling, which has opened new opportunities to develop safer therapeutic agents.
The microtubule motor dynein is regulated by lissencephaly-1 (Lis1) at several points during its complex activation process. Two papers reveal the molecular mechanism for two steps: the beginning, when Lis1 acts as a wedge to disrupt dynein’s autoinhibited conformation; and the end, when microtubule binding ejects Lis1 from the motor.
New cryo-electron microscopy (cryo-EM) structures of CDP- and CDP-choline-bound choline phosphotransferase 1 (CHPT1) and choline/ethanolamine phosphotransferase 1 (CEPT1), involved in the metabolism of the two main lipids in eukaryotic cell membranes, capture the membrane proteins at resolution <4 Å, sufficient to gain mechanistic insights into these enzymes.
The development of an epigenetics-focused, CRISPR-based high-content functional genomics screening platform provides insight into chromatin regulation and uncovers a potential strategy to treat an aggressive type of leukemia.
New work shows that in mammals, the iDDR motif of telomere factor TRF2 inhibits the MRE11–RAD50–NBS1 (MRN) complex at chromosome ends through a direct iDDR–RAD50 interaction. Unrelated protein motifs in yeasts inhibit MRN functions via an analogous mechanism, suggesting a convergent evolution in eukaryotes to control MRN action at telomeres.