HP1a promotes chromatin liquidity and drives spontaneous heterochromatin compartmentalization.

Unlabelled: Compartmentalization of the nucleus into heterochromatin and euchromatin is highly conserved across eukaryotes. Constitutive heterochromatin (C-Het) constitutes a liquid-like condensate that packages the repetitive regions of the genome through the enrichment of histone modification H3K9me3 and recruitment of its cognate reader protein Heterochromatin Protein-1 (HP1a). The ability for well-ordered nucleosome arrays and HP1a to independently form biomolecular condensates suggests that the emergent material properties of C-Het compartments may contribute to its functions such as force-buffering, dosage-dependent gene silencing, and selective permeability.

Anisotropic scrunching of SMC with a baton-pass mechanism.

DNA-loop extrusion is considered to be a universal principle of structural maintenance of chromosome (SMC) proteins with regard to chromosome organization. Despite recent advancements in structural dynamics studies that involve the use of cryogenic-electron microscopy (Cryo-EM), atomic force microscopy (AFM), etc., the precise molecular mechanism underlying DNA-loop extrusion by SMC proteins remains the subject of ongoing discussions.

MORC2 phosphorylation fine tunes its DNA compaction activity.

Variants in the poorly characterised oncoprotein, MORC2, a chromatin remodelling ATPase, lead to defects in epigenetic regulation and DNA damage response. The C-terminal domain (CTD) of MORC2, frequently phosphorylated in DNA damage, promotes cancer progression, but its role in chromatin remodelling remains unclear. Here, we report a molecular characterisation of full-length, phosphorylated MORC2, demonstrating its preference for binding open chromatin and functioning as a DNA sliding clamp.

Mechanism of phase condensation for chromosome architecture and function.

Chromosomal phase separation is involved in a broad spectrum of chromosome organization and functional processes. Nonetheless, the intricacy of this process has left its molecular mechanism unclear. Here, we introduce the principles governing phase separation and its connections to physiological roles in this context.

Molecular basis for SOX2-dependent regulation of super-enhancer activity.

Pioneer transcription factors (TFs) like SOX2 are vital for stemness and cancer through enhancing gene expression within transcriptional condensates formed with coactivators, RNAs and mediators on super-enhancers (SEs). Despite their importance, how these factors work together for transcriptional condensation and activation remains unclear. SOX2, a pioneer TF found in SEs of pluripotent and cancer stem cells, initiates SE-mediated transcription by binding to nucleosomes, though the mechanism isn't fully understood.

Current working models of SMC-driven DNA-loop extrusion.

Structural maintenance of chromosome (SMC) proteins play a key roles in the chromosome organization by condensing two meters of DNA into cell-sized structures considered as the SMC protein extrudes DNA loop. Recent sequencing-based high-throughput chromosome conformation capture technique (Hi-C) and single-molecule experiments have provided direct evidence of DNA-loop extrusion. However, the molecular mechanism by which SMCs extrude a DNA loop is still under debate.

Requirement of Cholesterol for Calcium-Dependent Vesicle Fusion by Strengthening Synaptotagmin-1-Induced Membrane Bending.

Cholesterol is essential for neuronal activity and function. Cholesterol depletion in the plasma membrane impairs synaptic transmission. However, the molecular mechanisms by which cholesterol deficiency leads to defects in vesicle fusion remain poorly understood.

SMC complexes can traverse physical roadblocks bigger than their ring size.

Ring-shaped structural maintenance of chromosomes (SMC) complexes like condensin and cohesin extrude loops of DNA. It remains, however, unclear how they can extrude DNA loops in chromatin that is bound with proteins. Here, we use in vitro single-molecule visualization to show that nucleosomes, RNA polymerase, and dCas9 pose virtually no barrier to loop extrusion by yeast condensin.

Condensin extrudes DNA loops in steps up to hundreds of base pairs that are generated by ATP binding events.

The condensin SMC protein complex organizes chromosomal structure by extruding loops of DNA. Its ATP-dependent motor mechanism remains unclear but likely involves steps associated with large conformational changes within the ∼50 nm protein complex. Here, using high-resolution magnetic tweezers, we resolve single steps in the loop extrusion process by individual yeast condensins.

Current Understanding of Molecular Phase Separation in Chromosomes.

Biomolecular phase separation denotes the demixing of a specific set of intracellular components without membrane encapsulation. Recent studies have found that biomolecular phase separation is involved in a wide range of cellular processes. In particular, phase separation is involved in the formation and regulation of chromosome structures at various levels.

Extreme parsimony in ATP consumption by 20S complexes in the global disassembly of single SNARE complexes.

Fueled by ATP hydrolysis in N-ethylmaleimide sensitive factor (NSF), the 20S complex disassembles rigid SNARE (soluble NSF attachment protein receptor) complexes in single unraveling step. This global disassembly distinguishes NSF from other molecular motors that make incremental and processive motions, but the molecular underpinnings of its remarkable energy efficiency remain largely unknown. Using multiple single-molecule methods, we found remarkable cooperativity in mechanical connection between NSF and the SNARE complex, which prevents dysfunctional 20S complexes that consume ATP without productive disassembly.

Bridging-induced phase separation induced by cohesin SMC protein complexes.

Structural maintenance of chromosome (SMC) protein complexes are able to extrude DNA loops. While loop extrusion constitutes a fundamental building block of chromosomes, other factors may be equally important. Here, we show that yeast cohesin exhibits pronounced clustering on DNA, with all the hallmarks of biomolecular condensation.

Publisher Correction: The condensin holocomplex cycles dynamically between open and collapsed states.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The condensin holocomplex cycles dynamically between open and collapsed states.

Structural maintenance of chromosome (SMC) protein complexes are the key organizers of the spatiotemporal structure of chromosomes. The condensin SMC complex has recently been shown to be a molecular motor that extrudes large loops of DNA, but the mechanism of this unique motor remains elusive. Using atomic force microscopy, we show that budding yeast condensin exhibits mainly open 'O' shapes and collapsed 'B' shapes, and it cycles dynamically between these two states over time, with ATP binding inducing the O to B transition.

Models of synaptotagmin-1 to trigger Ca -dependent vesicle fusion.

Vesicles in neurons and neuroendocrine cells store neurotransmitters and peptide hormones, which are released by vesicle fusion in response to Ca -evoking stimuli. Synaptotagmin-1 (Syt1), a Ca sensor, mediates ultrafast exocytosis in neurons and neuroendocrine cells. After vesicle docking, Syt1 has two main groups of binding partners: anionic phospholipids and the SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) complex.

Reconstruction of LPS Transfer Cascade Reveals Structural Determinants within LBP, CD14, and TLR4-MD2 for Efficient LPS Recognition and Transfer.

Lipopolysaccharide (LPS), the major component of the outer membrane of Gram-negative bacteria, binds Toll-like receptor 4 (TLR4)-MD2 complex and activates innate immune responses. LPS transfer to TLR4-MD2 is catalyzed by both LPS binding protein (LBP) and CD14. To define the sequential molecular interactions underlying this transfer, we reconstituted in vitro the entire LPS transfer process from LPS micelles to TLR4-MD2.

Review: Progresses in understanding N-ethylmaleimide sensitive factor (NSF) mediated disassembly of SNARE complexes.

N-ethylmaleimide sensitive factor (NSF) is a key protein of intracellular membrane traffic. NSF is a highly conserved protein belonging to the ATPases associated with other activities (AAA+ proteins). AAA+ share common domains and all transduce ATP hydrolysis into major conformational movements that are used to carry out conformational work on client proteins.

Spring-loaded unraveling of a single SNARE complex by NSF in one round of ATP turnover.

During intracellular membrane trafficking, N-ethylmaleimide-sensitive factor (NSF) and alpha-soluble NSF attachment protein (α-SNAP) disassemble the soluble NSF attachment protein receptor (SNARE) complex for recycling of the SNARE proteins. The molecular mechanism by which NSF disassembles the SNARE complex is largely unknown. Using single-molecule fluorescence spectroscopy and magnetic tweezers, we found that NSF disassembled a single SNARE complex in only one round of adenosine triphosphate (ATP) turnover.

Plasma pharmacokinetics and metabolism of the antitumour drug candidate 2'-benzoyloxycinnamaldehyde in rats.

The pharmacokinetics and metabolism of 2'-benzoyloxycinnamaldehyde (BCA) was characterized in male Sprague-Dawley rats as part of the preclinical evaluations for developing this compound as an antitumour agent. BCA was not detected in the plasma following either intravenous or oral dose, whereas its putative metabolites 2'-hydroxycinnamaldehyde (HCA) and o-coumaric acid were present at considerable levels. In separate pharmacokinetics studies, HCA exhibited a high systemic clearance and a large volume of distribution, whereas both pharmacokinetic parameters were much lower for o-coumaric acid.