Trends in Biochemical Sciences最新文献

In this piece, we use an antibody inventory system to exemplify the potential benefits of laboratory organization in research environments. We highlight how inventories can support resource accessibility and strengthen a sense of independence for scientists, especially those new to research environments.

Molecular de-extinction is an innovative science aiming to discover, synthesize, and characterize molecules throughout evolution. Recent work by Ferreira et al. involved mining ancient genomes to search for antimicrobial defensins. They discovered six ancient β-defensins, revealing their evolutionary history and uncovering their structural and biochemical properties, which could feed medical applications.

Necroptosis is a mode of programmed cell death executed by the mixed lineage kinase domain-like (MLKL) pseudokinase following its activation by the upstream receptor-interacting protein kinase-3 (RIPK3), subsequent to activation of death, Toll-like, and pathogen receptors. The pathway originates in innate immunity, although interest has surged in therapeutically targeting necroptosis owing to its dysregulation in inflammatory diseases. Here, we explore how protein conformation and higher order assembly of the pathway effectors - Z-DNA-binding protein-1 (ZBP1), RIPK1, RIPK3, and MLKL - can be modulated by post-translational modifications, such as phosphorylation, ubiquitylation, and lipidation, and intermolecular interactions to tune activities and modulate necroptotic signaling flux. As molecular level knowledge of cell death signaling grows, we anticipate targeting the conformations of key necrosomal effector proteins will emerge as new avenues for drug development.

The Crabtree effect in yeast, where cells prefer fermentation over respiration in high -glucose environments, is associated with mitochondrial repression, but the molecular mechanisms were previously unclear. Recently, Vengayil et al. revealed that knocking out the ubp3 gene, encoding a deubiquitinase enzyme, mitigates the Crabtree effect by increasing mitochondrial phosphate levels.

The molecular chaperones HSP70 and HSP90 play key roles in proteostasis by acting as adapters; they bind to a 'client' protein, often with the assistance of cochaperones, and then recruit additional cochaperones that promote specific fates (e.g., folding or degradation). One family of cochaperones contains a region termed the tetratricopeptide repeat with carboxylate clamps (CC-TPRs) domain. These domains bind to an EEVD motif at the C-termini of cytoplasmic HSP70 and HSP90 proteins, bringing them into proximity to chaperone-bound clients. It has recently become clear that CC-TPR proteins also bind to 'EEVD-like' motifs in non-chaperone proteins, circumventing the need for HSP70s or HSP90s. We provide an overview of the chaperone-dependent and -independent roles of CC-TPR proteins and discuss how, together, they shape proteostasis.

Limited proteolysis coupled to mass spectrometry (LiP-MS) has emerged as a powerful proteomic tool for studying protein conformations. Since its introduction in 2014, LiP-MS has expanded its scope to explore complex biological systems and shed light on disease mechanisms, and has been used for protein drug research. This review discusses the evolution of the technique, recent technical advances, including enhanced protocols and integration of machine learning, and diverse applications across various experimental models. Despite its achievements, challenges in protein extraction and conformotypic peptide identification remain. Ongoing methodological refinements will be crucial to overcome these challenges and enhance the capabilities of the technique. However, LiP-MS offers significant potential for future discoveries in structural proteomics and medical research.

Amyloids are filamentous protein aggregates that have traditionally been associated with neurodegenerative diseases, although they are also known to play pivotal functional roles across diverse forms of life. Although the cross-β structure has represented the hallmark of amyloidal assemblies, a cross-α structure was recently characterized as a functional microbial amyloid, and further work has shown that de novo designed sequences also assemble into cross-α amyloids, emphasizing cross-α as an alternative paradigm for self-assembly into ordered aggregates. In this review, we summarize recent discoveries of cross-α amyloids both in nature and artificially designed systems, and we describe their fundamental structural organization, self-assembly mechanisms, and biological functions. Finally, we outline the future opportunities for research and development in this potential field.

Ubiquitin (Ub) and ubiquitin-like (UbL) modifications are critical regulators of multiple cellular processes in eukaryotes. These modifications are dynamically controlled by proteases that balance conjugation and deconjugation. In eukaryotes, these proteases include deubiquitinases (DUBs), mostly belonging to the CA-clan of cysteine proteases, and ubiquitin-like proteases (ULPs), belonging to the CE-clan proteases. Intriguingly, infectious bacteria exploit the CE-clan protease fold to generate deubiquitinating activities to disarm the immune system and degradation defenses of the host during infection. In this review, we explore the substrate preferences encoded within the CE-clan proteases and the structural determinants in the protease fold behind its selectivity, in particular those from infectious bacteria and viruses. Understanding this protease family provides crucial insights into the molecular mechanisms underlying infection and transmission of pathogenic organisms.

The Nrf1/Nfe2L1 transcription factor is a master regulator of proteasome biogenesis. New work by Yoshida and colleagues reveals a surprising mechanism by which ubiquitination of N-glycosylated Nrf1 controls its function.