Articles in 2023

An Ago2^HA/HA mouse model combined with super-resolution microscopy, molecular and biochemical assays allowed us to stringently characterize AGO2 regulation in vivo. We found that in quiescent splenocytes, AGO2 localizes almost exclusively to the nucleus, where it binds to the RNA of young mobile transposons and represses their expression through its catalytic domain.

Here the authors show that, in the absence of Pi3K–AKT–mTOR signaling, AGO2 accumulates in the nucleus of quiescent cells, where it binds to young retrotransposons and represses their expression.

The human ATPase p97 (also known as VCP) unfolds protein substrates by translocating them through its central channel. This process is highly regulated by numerous adapter proteins. Structures of p97 in complex with the unusual adapter UBXD1 reveal how this protein coordinates p97 hexamer remodeling and ring opening by expansive interactions across multiple p97 protomers.

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.

Mao et al. reported ribosomal frameshifting events shortly after start codon selection, which is influenced by the sequence context and controlled by initiation factor eIF5B. This translational ‘noise’ is increased in response to nutrient starvation.

Extensive mutational analyses of ferroptosis suppressor protein-1 (FSP1) reveal its molecular mechanism in ferroptosis prevention and uncover the mechanism of action of the FSP1 inhibitor iFSP1 and a new species-independent FSP1 inhibitor, viFSP1.

Many multipass membrane proteins are not fully inserted into the membrane when translation ends. Wu et al. now show that a membrane insertase called EMC can facilitate maturation of these proteins by post-translationally completing their insertion.

Cryogenic electron microscopy structures reveal how the immunophilin co-chaperones, FKBP51 and FKBP52, each engage Hsp90–client complexes to directly stabilize a folded, ligand-bound client, the glucocorticoid receptor, and promote the next stage of client maturation.

Braxton et al. report structures of human p97/VCP bound to the UBXD1 adaptor involved in autophagy. The structures reveal how UBXD1 utilizes multiple interaction domains to remodel and open the hexamer ring, revealing its role in p97 regulation.

The authors reveal the architecture and functional annotation of large immunophilin-containing Hsp90–apo-GR complexes by systematic incorporation of photocrosslinker inside human cells and show that FKBP51 and FKBP52 differentially interact with the apo-GR.

Using cryo-EM, here the authors structurally delineate the Elongin–RNA polymerase II holocomplex. They show that Elongin allosterically regulates the transcribing RNA polymerase II via a latch that affects its conformational mobility.

The authors show that the lncRNA-derived microprotein SMIMP, which is shown to promote tumor formation, regulates cohesin core subunit binding to cis-regulatory elements and alters the expression of tumor-suppressive cell cycle regulators.

Here, Kasaragod et al. solve structures of the GABA_A receptor α5 subunit in complex with different classes of positive and negative allosteric modulators to explain the binding modes and the molecular basis of selectivity.

This study revealed the mechanism by which the E3 ligase Bre1 directs monoubiquitination of histone H2B at K123 by the E2 ubiquitin-conjugating enzyme Rad6. Comparison with other dimeric E3 ligases suggests a pivot-like mechanism in which one subunit ‘tunes’ the specificity for particular histone residues.

Here, using single molecule experiments, the authors show that the mechanical stability of cohesin encircling DNA is determined by its hinge domain that disengages at ~20 pN force, providing a framework for how cohesin counteracts spindle-generated tension during mitosis.

Glutaminase is a mitochondrial complex that deaminates glutamine to form glutamate. Here the authors investigate inorganic-phosphate-induced enzyme filamentation, revealing an allosteric mechanism and roles of filamentous glutaminase in mitochondrial morphology and recycling.

Reimer et al. used cryo-EM and cellular assays to reveal the structural and regulatory features that distinguish LRRK1 from LRRK2, and placed these features in the context of the evolution of the LRRK family of proteins.

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.