A channel for calcium: Maintaining the correct balance of calcium concentrations between the cytosol and the mitochondria is essential for cellular physiology. A calcium-selective channel called the mitochondrial calcium uniporter (MCU) mediates calcium entry into mitochondria. Yoo et al. report the high-resolution structure of MCU from Neurospora crassa. The channel is formed by four MCU protomers with differing symmetry between the soluble and membrane domains. The structure, together with mutagenesis, suggests that two acidic rings inside the channel provide the selectivity for calcium. Science , this issue p. 506

Lipopolysaccharide (LPS) triggers deleterious systemic inflammatory responses when released into the circulation. LPS‐binding protein (LBP) in the serum plays an important role in modifying LPS toxicity by facilitating its interaction with LPS signaling receptors, which are expressed on the surface of LPS‐responsive cells. We have previously demonstrated that high mobility group box 1 (HMGB1) can bind to and transfer LPS, consequently increasing LPS‐induced TNF‐α production in human peripheral blood mononuclear cells (PBMCs). We report here on the identification of two LPS‐binding domains within HMGB1. Furthermore, using 12 synthetic HMGB1 peptides, we define the LPS‐binding regions within each domain. Among them, synthetic peptides HPep1 and HPep6, which are located in the A and B box domains of HMGB1, bind to the polysaccharide and lipid A moieties of LPS respectively. Both HPep1 and HPep6 peptides inhibited binding of LPS to LBP and HMGB1, LBP‐mediated LPS transfer to CD14, and cellular uptake of LPS in RAW264.7 cells. These peptides also inhibited LPS‐induced TNF‐α release in human PBMCs and induced lower levels of TNF‐α in the serum in a subclinical endotoxemia mouse model. These results indicate that HMGB1 has two LPS‐binding peptide regions that can be utilized to design anti‐sepsis or LPS‐neutralizing therapeutics.

Parkinson's disease (PD) is a common neurodegenerative disease that involves the deterioration of dopaminergic neurons in the substantia nigra pars compacta. Although the etiology of PD remains poorly understood, recent genetic, postmortem, and experimental evidence shows that abnormal protein accumulation and subsequent aggregate formation are prominent features of both sporadic and familial PD. While proteasome dysfunction is observed in PD, diverse mutations in theparkingene are linked to early-onset autosomal-recessive forms of familial PD. We demonstrate that parkin, an E3 ubiquitin ligase, activates the 26S proteasome in an E3 ligase activity-independent manner. Furthermore, an N-terminal ubiquitin-like domain within parkin is critical for the activation of the 26S proteasome through enhancing the interaction between 19S proteasomal subunits, whereas the PD-linked R42P mutant abolishes this action. The current findings point to a novel role for parkin for 26S proteasome assembly and suggest that parkin mutations contribute to the proteasomal dysfunction in PD.

Danbi Yoon, Ju Heun Moon, Anna Cho, Hyejoon Boo, Jeong Seok Cha*, Yoonji Lee*, and Jiho Yoo*. Mol. Cells 2023;46:337-44. https://doi.org/10.14348/molcells.2023.0001

Quercetin, a prevalent plant flavonoid, demonstrates many biological functions through its interaction with distinct protein targets. Recent structural investigations of protein–quercetin complexes have elucidated the molecular mechanism behind these actions. This paper presents a thorough structural analysis of experimentally established protein–quercetin complex structures published to date. The structure of the protein–quercetin complex elucidates the molecular mechanism by which quercetin influences protein function. These structures illustrate how quercetin’s chemical characteristics facilitate diverse modes of action by enabling particular interactions with the target protein. This structural knowledge provides the molecular foundation for comprehending quercetin’s biological roles and indicates avenues for future structural investigations of flavonoid–protein complexes, especially those with ambiguous molecular processes.