Ion channels are thought to have fixed oligomeric stoichiometries tightly linked to function, yet we recently observed varied channel oligomeric states and transitions between them. This ‘oligomeric plasticity’ may be a structure–function mechanism whereby membrane proteins diversify function, regulate activity and respond dynamically to cues.
Mammalian SWI/SNF complexes, also known as BRG1/BRM-associated factor (BAF) complexes, are ATP-dependent chromatin remodelers that mobilize nucleosomes to regulate chromatin accessibility and the transcriptional programs that establish cell identity and responses to environmental stimuli. In this Review, we discuss recent insights into the structural organization and modular assembly of BAF complexes, examine how they are recruited to chromatin by transcription factors, noncoding RNAs and histone modifications and describe their roles in transcription, from RNA polymerase II pausing and R-loop homeostasis to enhancer activation and phase separation. Throughout, we emphasize unifying principles that operate across physiological and pathological contexts. This Review discusses recent insights into the structure and assembly of mammalian SWI/SNF chromatin remodelers, their recruitment to chromatin and their roles in transcription.
Circular RNAs (circRNAs) are emerging as important regulators in mammalian cells and promising substrates for RNA therapeutics, yet the trans-acting factors governing their metabolism remain poorly defined. Here we systematically evaluate 730 RNA-binding proteins (RBPs) using a tethered reporter assay and identify 281 RBPs that significantly modulate circRNA activity. Follow-up assays implicate these RBPs across key stages of the circRNA life cycle, including biogenesis, nuclear export, degradation and translation. We identify seven RBPs for tethered translation enhancement of therapeutically applicable circRNA vectors and highlight LARP4B as a potent enhancer of exogenous circRNA translation across multiple internal ribosomal entry sites and cell types. We uncover an evolutionarily conserved role for RBM15 in circRNA biogenesis in fly, mouse and human, further demonstrating a role in circRNA nuclear retention, and that perturbing RBM15 sites with dCasRx or antisense oligonucleotides modulates endogenous circRNA expression. Together, our study provides a global view of circRNA trans-regulation and describes practical entry points for therapeutic development. This study systematically evaluates proteins that control circular RNA production, stability and translation, revealing new regulators and strategies to enhance or suppress circular RNA activity for therapeutic development.
Nearly half of the ~5,000 human membrane proteins need to assemble into stoichiometric complexes as part of their biogenesis at the endoplasmic reticulum (ER) membrane. How ER-resident biogenesis factors coordinate membrane insertion, folding and assembly is not well understood. Here we demonstrate that the human ER membrane protein complex (EMC) insertase additionally acts as a chaperone to facilitate the assembly of heterotrimeric voltage-gated calcium channels (Cav). Using function-separating mutations and inhibitory nanobodies, we show that nascent Cav channels are degraded prematurely when EMC’s chaperone function is selectively perturbed. Blocking EMC’s chaperone function impaired Cav-dependent cardiomyocyte contraction. EMC engagement of the pore-forming Cav α-subunit occurred cotranslationally and required the Cav α-subunit’s first transmembrane domain bundle to protrude from the nascent ribosome–multipass translocon complex. Our findings establish a chaperone function for the EMC and suggest that biogenesis of multibundle membrane proteins may require a highly orchestrated, cotranslational interplay among ER biogenesis factors. Stanton et al. show that the human endoplasmic reticulum membrane protein complex (EMC) engages nascent calcium channels cotranslationally as a chaperone as part of a large ribosome–multipass translocon–EMC supercomplex. Loss of this function impairs channel biogenesis and disrupts cardiomyocyte contraction.
Bil Clemons is the Hanisch Memorial Professor of Biochemistry at Caltech, where he leads a research group applying structural biology approaches to study membrane protein biogenesis and peptidoglycan biosynthesis in bacteria. He is also a scientist-in-residence at the Biohub. Here, I asked Bil about his journey to becoming the scientist he is today, advances in structural biology, and the field of protein biogenesis and balancing great science with humanity.
