Trends in Biochemical Sciences最新文献

Enzymes can usually be unambiguously assigned to one of seven classes specifying the basic chemistry of their catalyzed reactions. Less frequently, two or more reaction classes are catalyzed by a single enzyme within one active site. Two examples are an isomerohydrolase and an isomero-oxygenase that catalyze isomerization-coupled reactions crucial for production of vision-supporting 11-cis-retinoids. In these enzymes, isomerization is obligately paired and mechanistically intertwined with a second reaction class. A handful of other enzymes carrying out similarly coupled isomerization reactions have been described, some of which have been subjected to detailed structure–function analyses. Herein we review these rarefied enzymes, focusing on the mechanistic and structural basis of their reaction coupling with the goal of revealing catalytic commonalities.

The dynamics behavior of a protein is essential for its functionality. Here, Doucet et al. demonstrate how the evolutionary analysis of conformational pathways within a protein family serves to identify common core scaffolds that accommodate branch-specific functional regions controlled by flexibility switches, offering a model for evolutionary-dynamics based protein design.

Lytic cell death culminates in cell swelling and plasma membrane rupture (PMR). The cellular contents released, including proteins, metabolites, and nucleic acids, can act as danger signals and induce inflammation. During regulated cell death (RCD), lysis is actively initiated and can be preceded by an initial loss of membrane integrity caused by pore-forming proteins, allowing small molecules and cytokines to exit the cell. A recent seminal discovery showed that ninjurin1 (NINJ1) is the common executioner of PMR downstream of RCD, resulting in the release of large proinflammatory molecules and representing a novel target of cell death-associated lysis. We summarize recent developments in understanding membrane integrity and rupture of the plasma membrane with a focus on NINJ1.

Protein lipoylation, a crucial post-translational modification (PTM), plays a pivotal role in mitochondrial function and emerges as a key player in cell death through cuproptosis. This novel copper-driven cell death pathway is activated by excessive copper ions binding to lipoylated mitochondrial proteins, disrupting energy production and causing lethal protein aggregation and cell death. The intricate relationship among protein lipoylation, cellular energy metabolism, and cuproptosis offers a promising avenue for regulating essential cellular functions. This review focuses on the mechanisms of lipoylation and its significant impact on cell metabolism and cuproptosis, emphasizing the key genes involved and their implications for human diseases. It offers valuable insights into targeting dysregulated cellular metabolism for therapeutic purposes.

Designers' work processes are shaped by a four-phase ‘discover, define, develop, and deliver’ model that alternates between divergent and convergent thinking. We suggest consideration of this conceptual scaffold in ‘design sprint’ workshops for graduate students in the life sciences and in design to promote creativity, interdisciplinary collaboration, and knowledge cocreation.

Calcium is a crucial second messenger in the cell that is stored in organelles including lysosomes. Proteins that facilitate calcium entry to the lysosome were unknown. A recent report by Zajac et al. identified TMEM165 as a proton-activated calcium importer on the lysosome, thus discovering a key player in subcellular calcium homeostasis.

Transient receptor potential (TRP) channels are implicated in a wide array of mechanotransduction processes. However, a question remains whether TRP channels directly sense mechanical force, thus acting as primary mechanotransducers. We use several recent examples to demonstrate the difficulty in definitively ascribing mechanosensitivity to TRP channel subfamilies. Ultimately, despite being implicated in an ever-growing list of mechanosignalling events in most cases limited robust or reproducible evidence supports the contention that TRP channels act as primary transducers of mechanical forces. They either (i) possess unique and as yet unspecified structural or local requirements for mechanosensitivity; or (ii) act as mechanoamplifiers responding downstream of the activation of a primary mechanotransducer that could include Ca²⁺-permeable mechanosensitive (MS) channels or other potentially unidentified mechanosensors.