Trends in Biochemical Sciences最新文献

Molecular glue degraders (MGDs) represent a unique class of targeted protein degradation (TPD) modalities. By facilitating protein-protein interactions between E3 ubiquitin ligases and neo-substrates, MGDs offer a novel approach to target previously undruggable or insufficiently drugged disease-causing proteins. Here, we present an overview of recently reported MGDs, highlighting their diverse mechanisms, and we discuss mechanism-based strategies to discover new MGDs and neo-substrates. These strategies include repurposing existing E3 ubiquitin ligase-targeting ligands, screening for novel binders to proteins of interest, and leveraging functional genomics and quantitative proteomics to probe the MGD mechanism of action. Despite their historically serendipitous discovery, MGDs are on their way to being rationally designed to deplete undesired proteins by purposely altering the evolutionarily conserved ligase:substrate interactions.

Pyrenoids are the key component of one of the most abundant biological CO₂ concentration mechanisms found in nature. Pyrenoid-based CO₂-concentrating mechanisms (pCCMs) are estimated to account for one third of global photosynthetic CO₂ capture. Our molecular understanding of how pyrenoids work is based largely on work in the green algae Chlamydomonas reinhardtii. Here, we review recent advances in our fundamental knowledge of the biogenesis, architecture, and function of pyrenoids in Chlamydomonas and ongoing engineering biology efforts to introduce a functional pCCM into chloroplasts of vascular plants, which, if successful, has the potential to enhance crop productivity and resilience to climate change.

During heat shock (HS), cells orchestrate a gene expression program that promotes the synthesis of HS proteins (HSPs) while simultaneously repressing the synthesis of other proteins, including growth-promoting housekeeping proteins. Recent studies show that mRNAs encoding housekeeping proteins, along with associated processing factors, form macromolecular assemblies during HS. These assemblies inhibit transcription, nuclear export, and translation of housekeeping mRNAs, and coincide with structural rearrangements in proteins. These findings reveal a mechanism linking temperature sensitivity through structural rearrangements and macromolecular assembly to the 'shut down' of housekeeping protein synthesis. This review delves into recent findings in yeast, with a focus on macromolecular assembly, offering perspectives into mechanisms that regulate gene expression during HS and how these processes may be conserved.

Studies of enzymes catalyzing carbon-fluorine (C-F) bond cleavage have focused largely on a limited number of native microbial hydrolases that are reactive with the natural product fluoroacetate. Driven by widespread interest in biodegrading commercial fluorinated compounds, many of which are known as per- and polyfluorinated alkyl substances (PFAS), it is necessary to identify and engineer new enzymes. For example, some hydrolases react with -CF₂- moieties, a common functionality in PFAS. Additional enzymatic C-F cleaving mechanisms catalyzed by reductases, lyases, and oxygenases have been identified via screening. Screening and evolving PFAS defluorination in bacteria is inhibited by the obligate release of toxic fluoride from C-F cleavage. Engineering greater fluoride tolerance in bacteria is a problem that must be solved in tandem with enzyme improvement.

Recently developed KRAS inhibitors have delivered clinical benefits but their antitumor efficacy remains limited. A recent study by Klomp et al. reports an unprecedentedly comprehensive profiling of protein phosphorylation dependent on the KRAS pathway and generates new insights and directions to improve the efficacy of KRAS-targeted therapies.

G-protein-coupled receptors (GPCRs) are the largest family of cell receptors. They mediate the effects of a multitude of endogenous and exogenous cues, are deeply involved in human physiology and disease, and are major pharmacological targets. Whereas GPCRs were long thought to signal exclusively at the plasma membrane, research over the past 15 years has revealed that they also signal via classical G-protein-mediated pathways on membranes of intracellular organelles such as endosomes and the Golgi complex. This review provides an overview of recent advances and emerging concepts related to endomembrane GPCR signaling, as well as ongoing research aimed at a better understanding of its mechanisms, physiological relevance, and potential therapeutic applications.

Protein kinases regulate many intracellular processes, and their dysregulation causes cancers and other diseases. This review focuses on the atypical alpha-kinase 1 (ALPK1), which is activated in mammalian cells by nucleoside diphosphate heptoses (ADP-heptose, UDP-heptose, and CDP-heptose) produced by microbial pathogens but not by mammalian cells. Mutations in human ALPK1 cause ROSAH syndrome and spiradenoma, which result from an alteration in its specificity for nucleoside diphosphate heptoses, causing aberrant activation by mammalian nucleoside diphosphate sugars without microbial infection. These may be the first diseases caused by altered specificity of an enzyme for its allosteric activators and has suggested ways in which selective drugs could be developed to treat them without compromising the innate immune system.

DNA is constantly subject to damage from endogenous and exogenous factors, leading to mutations and disease. While DNA is traditionally repaired in the nucleus, Lascaux et al. reveal a novel role for the lysosome in DNA repair, demonstrating that topoisomerase 1 (TOP1) cleavage complex (TOP1cc) DNA lesions are degraded via TEX264-mediated selective autophagy.

Defects in the tumor suppressor protein p53 are found in the majority of cancers. The p53 protein (393 amino acids long) contains the folded DNA-binding domain (DBD) and tetramerization domain (TET), with the remainder of the sequence being intrinsically disordered. Since cancer-causing mutations occur primarily in the DBD, this has been the focus of most of the research on p53. However, recent reports show that the disordered N-terminal activation domain (NTAD) and C-terminal regulatory domain (CTD) function synergistically with the DBD to regulate p53 activity. We propose a mechanistic model in which intermolecular and intramolecular interactions of the disordered regions, modulated by post-translational modifications, perform a central role in the regulation and activation of p53 in response to cellular stress.