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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.
Inactivation of one of the two female X chromosomes involves condensing it into a repressive subnuclear territory, which is depleted of transcriptional components and undergoes late-stage DNA replication. Two new studies unravel how compartmentalization of the inactive mammalian X chromosome affects transcription and DNA replication.
Pioneer transcription factors access gene regulatory sites embedded within chromatin. They drive gene expression programs vital for cell fate decisions and cellular reprogramming, but how they engage nucleosomal sites at the molecular level is unclear. New results show that they engage histones and collaborate to overcome the nucleosome barrier.
NuA4 is a highly conserved histone acetyltransferase complex that functions in transcription and DNA repair. Four groups have recently determined the structure of NuA4 from two different yeasts using cryo-EM, revealing important mechanistic details of its function and allowing a detailed comparison to the related SAGA complex.
Unlike autosomal genes, X-linked genes are expressed from only one copy in both male and female mammals. How cells increase X-linked gene expression to match autosomal levels is unclear. New evidence suggests that lower levels of RNA modifications on X chromosome-derived transcripts critically regulate mRNA stability and help to balance X-to-autosome gene expression levels.
