Biological Chemistry最新文献

The phylum Euglenozoa, within the Eukaryote domain, includes diverse protists such as the medically significant kinetoplastids, characterized by their unique kinetoplast DNA. Both kinetoplastids and their sister class Diplonemea possess glycosomes - specialized microbodies that compartmentalize glycolysis and other metabolic pathways. Glycosomes likely evolved in a common ancestor of kinetoplastid and diplonemids, conferring metabolic flexibility and reducing cellular toxicity. These organelles are essential for parasite survival and thus, represent promising drug targets for treating kinetoplastid diseases. While the basic principles of peroxisome and glycosome biogenesis are conserved, distinct features in glycosome biogenesis machinery and a lower level of sequence conservation enables pathogen specific drug design for developing new therapies. This review summarizes our current knowledge on glycosome biogenesis, recent advances, and therapeutic potential for treating trypanosomatid infections.

Dendritic spines are the postsynaptic compartment of most excitatory synapses in the vertebrate brain. Their morphology is defined by a complex actin scaffold consisting of branched and unbranched actin filaments (F-actin), which constitute the major structural component of dendritic spines. During brain development, dendritic spines arise from dendritic filopodia, motile finger-like dendritic protrusions, whose morphology is also defined by an actin scaffold. The organization of the actin scaffold as well as its dynamic behavior in both dendritic filopodia and dendritic spines requires the coordinated activity of actin binding proteins (ABP) that promote either assembly or disassembly of F-actin. Studies of the past two decades identified a number of ABP and upstream regulatory pathways that control the morphology of dendritic spines as well as their morphological changes associated with synaptic plasticity, the cellular basis for learning and memory. Instead, much less is known about actin regulatory mechanisms that control the formation and elongation of dendritic filopodia or the structural changes associated with their transition into dendritic spines. This review article highlights recent advances in the field by summarizing and discussing studies of the past few years that provided exciting novel insights into the molecular machinery that governs dendritic filopodia initiation and their maturation into dendritic spines.

The small protein family of VAMP-associated proteins (VAPs) have the unique position in cell biology as intracellular signposts for the Endoplasmic Reticulum (ER). VAP is recognised by a wide range of other proteins that use it to target the ER, either simply being recruited from the cytoplasm, or being recruited from separate organelles. The latter process makes VAP a component of many bridges between the ER and other compartments at membrane contact sites. The fundamental observations that identify VAP as the ER signpost have largely remained unchanged for over two decades. This review will describe how increased understanding of the special role of VAP in recent years has led to new discoveries: what constitutes the VAP family, how proteins bind to VAP, and which cellular functions connect to the ER using VAP. It will also describe the pitfalls that have led to difficulties determining how some proteins bind VAP and suggest some possibilities for future research.

The rapid spread of bacterial resistance to antibiotics necessitates the development of innovative strategies to enhance their efficacy. One promising approach is incorporating antimicrobial peptides (AMPs) to synergize antibiotics. Herein, we introduce pH-responsive nanoplexes of plant AMP and sodium alginate (Na-Alg) for the co-delivery of AMP and Vancomycin (VCM) against resistant bacteria. The optimal nanoplexes (VCM-Na-Alg/AMP) were characterized, revealing a particle size, polydispersity index, zeta potential, encapsulation efficiency, and loading capacity of 159.5 ± 1.150 nm, 0.149 ± 0.018, -23.1 ± 0.1 mV, 82.34 ± 0.07 %, and 24.03 ± 0.10 % w/w, respectively. The nanoplexes exhibited pH-dependent changes in size and accelerated VCM release at acidic pH. In vitro antibacterial studies demonstrated a 2-fold enhanced activity against Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) and a 5-fold greater MRSA biofilm eradication, compared to bare VCM. Furthermore, the in vivo antibacterial activity evaluated on a mice model of MRSA systemic infection demonstrated that the nanoplexes reduced MRSA burden by 5-fold in kidneys and 4-fold in liver and blood. The nanoplexes also exhibited reduced inflammation and improved tissue integrity in the treated subjects. These findings present VCM-Na-Alg/AMP as a novel strategy to augment the efficacy of antibiotics against resistant bacteria.

Polyamines are ubiquitous and essential for cellular physiology, yet their metabolic pathways and functions remain only partially understood. Polyamine oxidases (PAO) are key to elucidating their physiological roles. In the methylotrophic yeast Ogataea parapolymorpha, we identified three putative PAO-encoding genes. Biochemical characterization showed that two of them function as PAOs, whereas the third has unknown substrate specificity. In contrast to previously studied yeasts, including Saccharomyces cerevisiae, which contain only a single PAO, O. parapolymorpha harbors multiple and functionally distinct PAOs. These findings highlight an unexpected diversification of polyamine catabolism in yeast and suggest previously unrecognized roles of PAOs in cellular physiology.

The 76th Mosbacher Kolloquium focused on recent advances in machine learning applications for structural biology and protein design. It covered topics spanning artificial intelligence-driven protein structure prediction, integrative modeling, generative protein design, and general applications in life sciences. With strong participation, high-caliber talks, and a clear focus on the integration of AI in biomolecular research, the meeting underscored the transformative role of machine learning in molecular biosciences and provided a vibrant platform for knowledge exchange across disciplines and generations.

Mitochondria are essential for cellular metabolism, serving as the primary source of adenosine triphosphate (ATP). This energy is generated by the oxidative phosphorylation (OXPHOS) system located in the inner mitochondrial membrane. Impairments in this machinery are linked to serious human diseases, especially in tissues with high energy demands. Assembly of the OXPHOS system requires the coordinated expression of genes encoded by both the nuclear and mitochondrial genomes. The mitochondrial DNA encodes for 13 protein components, which are synthesized by mitochondrial ribosomes and inserted into the inner membrane during translation. Despite progress, key aspects of how mitochondrial gene expression is regulated remain elusive, largely due to the organelle's limited genetic accessibility. However, emerging technologies now offer new tools to manipulate various stages of this process. In this review, we explore recent strategies that expand our ability to target mitochondria genetically.

Mitochondrial function relies heavily on the proper targeting and insertion of nuclear-encoded proteins into the outer mitochondrial membrane (OMM), a process mediated by specialised biogenesis factors known as insertases. These insertases are essential for the membrane integration of α-helical OMM proteins, which contain one or multiple hydrophobic transmembrane segments. While the general mechanisms of mitochondrial protein import are well established, recent research has shed light on the diversity and evolutionary conservation of OMM insertases across eukaryotic lineages. In Saccharomyces cerevisiae, the mitochondrial import (MIM) complex, composed of Mim1 and Mim2, facilitates the integration of various α-helical OMM proteins, often in cooperation with import receptors such as Tom20 and Tom70. In Trypanosoma brucei, the functional MIM counterpart pATOM36 performs a similar role despite lacking sequence and structural homology, reflecting a case of convergent evolution. In mammals, MTCH2 has emerged as the principal OMM insertase, with MTCH1 playing a secondary, partially redundant role. This review provides a comparative analysis of these insertases, emphasising their conserved functionality, species-specific adaptations, and mechanistic nuances.

The mitochondrial solute carrier family, also called SLC25 family, comprises a group of structurally and evolutionary related transporters that are embedded in the mitochondrial inner membrane. About 35 and 53 mitochondrial carrier proteins are known in yeast and human cells, respectively, which transport nucleotides, metabolites, amino acids, fatty acids, inorganic ions and cofactors across the inner membrane. They are proposed to function by a common rocker-switch mechanism, alternating between conformations that expose substrate-binding pockets to the intermembrane space (cytoplasmic state) and to the matrix (matrix state). The substrate specificities of both states differ so that carriers can operate as antiporters, symporters or uniporters. Carrier proteins share a characteristic structure comprising six transmembrane domains and expose both termini to the intermembrane space. Most carriers lack N-terminal presequences but use carrier-specific internal targeting signals that direct them into mitochondria via a specific import route, known as the 'carrier pathway'. Owing to their hydrophobicity and aggregation-prone nature, the mistargeting of carriers can lead to severe proteotoxic stress and diseases. In this review article, we provide an overview about the structure, biogenesis and physiology of carrier proteins, focusing on baker's yeast where their biology is particularly well characterized.