Journal of Molecular Biology

The catalytic cycle of Enzyme I (EI), a phosphotransferase enzyme responsible for converting phosphoenolpyruvate (PEP) into pyruvate, is characterized by a series of local and global conformational rearrangements. This multistep process includes a monomer-to-dimer transition, followed by an open-to-closed rearrangement of the dimeric complex upon PEP binding. In the present study, we investigate the thermodynamics of EI dimerization using a range of high-pressure solution NMR techniques complemented by SAXS experiments...

Nearest neighbor thermodynamic parameters are widely used for RNA and DNA secondary structure prediction and to model thermodynamic ensembles of secondary structures. The Nearest Neighbor Database (NNDB) is a freely available web resource (https://rna.urmc.rochester.edu/NNDB) that provides the functional forms, parameter values, and example calculations. The NNDB provides the 1999 and 2004 set of RNA folding nearest neighbor parameters. We expanded the database to include a set of DNA parameters and a set of RNA parameters that includes m6 A in addition to the canonical RNA nucleobases...

A single protein structure is rarely sufficient to capture the conformational variability of a protein. Both bound and unbound (holo and apo) forms of a protein are essential for understanding its geometry and making meaningful comparisons. Nevertheless, docking or drug design studies often still consider only single protein structures in their holo form, which are for the most part rigid. With the recent explosion in the field of structural biology, large, curated datasets are urgently needed. Here, we use a previously developed application (AHoJ) to perform a comprehensive search for apo-holo pairs for 468,293 biologically relevant protein-ligand interactions across 27,983 proteins...

Plant C-glycosylated aromatic polyketides are important for plant and animal health. These are specialized metabolites that perform functions both within the plant, and in interaction with soil or intestinal microbes. Despite the importance of these plant compounds, there is still limited knowledge of how they are metabolized. The Gram-positive aerobic soil bacterium Deinococcus aerius strain TR0125 and other Deinococcus species thrive in a wide range of harsh environments. In this work, we identified a C-glycoside deglycosylation gene cluster in the genome of D...

Bacteriophage T4 gene 32 protein (gp32) is a single-stranded DNA (ssDNA) binding protein essential for DNA replication. gp32 forms stable protein filaments on ssDNA through cooperative interactions between its core and N-terminal domain. gp32's C-terminal domain (CTD) is believed to primarily help coordinate DNA replication via direct interactions with constituents of the replisome. However, the exact mechanisms of these interactions are not known, and it is unclear how tightly-bound gp32 filaments are readily displaced from ssDNA as required for genomic processing...

Cellular communication relies on the intricate interplay of signaling molecules, forming the Cell-cell Interaction network (CCI) that coordinates tissue behavior. Researchers have shown the capability of shallow neural networks in reconstructing CCI, given molecules' abundance in the Spatial Transcriptomics (ST) data. When encountering situations such as sparse connections in CCI and excessive noise, the susceptibility of shallow networks to these factors significantly impacts the accuracy of CCI reconstruction, resulting in subpar results...

IHMCIF (github.com/ihmwg/IHMCIF) is a data information framework that supports archiving and disseminating macromolecular structures determined by integrative or hybrid modeling (IHM), and making them Findable, Accessible, Interoperable, and Reusable (FAIR). IHMCIF is an extension of the Protein Data Bank Exchange/macromolecular Crystallographic Information Framework (PDBx/mmCIF) that serves as the framework for the Protein Data Bank (PDB) to archive experimentally determined atomic structures of biological macromolecules and their complexes with one another and small molecule ligands (e...

Interaction of transcription factor myocyte enhancer factor-2 (MEF2) family members with class IIa histone deacetylases (HDACs) has been implicated in a wide variety of diseases. Though considerable knowledge on this topic has been accumulated over the years, a high resolution and detailed analysis of the binding mode of multiple class IIa HDAC derived peptides with MEF2D is still lacking. To fulfil this gap, we report here the crystal structure of MEF2D in complex with double strand DNA and four different class IIa HDAC derived peptides, namely HDAC4, HDAC5, HDAC7 and HDAC9...

PrimPol is a human DNA primase-polymerase which restarts DNA synthesis beyond DNA lesions and non-B DNA structures blocking replication. Disfunction of PrimPol in cells leads to slowing of DNA replication rates in mitochondria and nucleus, accumulation of chromosome aberrations, cell cycle delay, and elevated sensitivity to DNA-damaging agents. A defective PrimPol has been suggested to be associated with the development of ophthalmic diseases, elevated mitochondrial toxicity of antiviral drugs and increased cell resistance to chemotherapy...

Membrane atg8ylation is a homeostatic process responding to membrane remodeling and stress signals. Membranes are atg8ylated by mammalian ATG8 ubiquitin-like proteins through a ubiquitylation-like cascade. A model has recently been put forward which posits that atg8ylation of membranes is conceptually equivalent to ubiquitylation of proteins. Like ubiquitylation, membrane atg8ylation involves E1, E2 and E3 enzymes. The E3 ligases catalyze the final step of atg8ylation of aminophospholipids in membranes. Until recently, the only known E3 ligase for membrane atg8ylation was ATG16L1 in a noncovalent complex with the ATG12-ATG5 conjugate...

Through an extensive literature survey, we have upgraded the Leaf Senescence Database (LSD v5.0; https://ngdc.cncb.ac.cn/lsd/), a curated repository of comprehensive senescence-associated genes (SAGs) and their corresponding mutants. Since its inception in 2010, LSD undergoes frequent updates to encompass the latest advances in leaf senescence research and its current version comprises a high-quality collection of 31,740 SAGs and 1,209 mutants from 148 species, which were manually searched based on robust experimental evidence and further categorized according to their functions in leaf senescence...

No abstract text is available yet for this article.

Dedicated translocase channels are nanomachines that often, but not always, unfold and translocate proteins through narrow pores across the membrane. Generally, these molecular machines utilize external sources of free energy to drive these reactions, since folded proteins are thermodynamically stable, and once unfolded they contain immense diffusive configurational entropy. To catalyze unfolding and translocate the unfolded state at appreciable timescales, translocase channels often utilize analogous peptide-clamp active sites...

The Mouse Variation Registry (MVAR) resource is a scalable registry of mouse single nucleotide variants and small indels and variant annotation. The resource accepts data in standard Variant Call Format (VCF) and assesses the uniqueness of the submitted variants via a canonicalization process. Novel variants are assigned a unique, persistent MVAR identifier; variants that are equivalent to an existing variant in the resource are associated with the existing identifier. Annotations for variant type, molecular consequence, impact, and genomic region in the context of specific transcripts and protein sequences are generated using Ensembl's Variant Effect Predictor (VEP) and Jannovar...

Skp2, the substrate recognition component of the SCFSkp2 ubiquitin ligase, has been implicated in the targeted destruction of a number of key cell cycle regulators and the promotion of S-phase. One of its critical targets is the Cyclin dependent kinase (Cdk) inhibitor p27, and indeed the overexpression of Skp2 in a number of cancers is directly correlated with the premature degradation of p27. Skp2 was first identified as a protein that interacts with Cyclin A in transformed cells, but its role in this complex has remained unclear...

Inorganic polyphosphate (polyP), the first high-energy compound on earth, defies its extreme compositional and structural simplicity with an astoundingly wide array of biological activities across all domains of life. However, the underlying mechanism of such functional pleiotropy remains largely elusive. In this review, we will summarize recent studies demonstrating that this simple polyanion stabilizes protein folding intermediates and scaffolds select native proteins. These functions allow polyP to act as molecular chaperone that protects cells against protein aggregation, as pro-amyloidogenic factor that accelerates both physiological and disease-associated amyloid formation, and as a modulator of liquid-liquid phase separation processes...

Regulation of neurotransmitter release during presynaptic plasticity underlies varied forms of information processing in the brain. Munc13s play essential roles in release via their conserved C-terminal region, which contains a MUN domain involved SNARE complex assembly, and control multiple presynaptic plasticity processes. Munc13s also have a variable N-terminal region, which in Munc13-1 includes a calmodulin binding (CaMb) domain involved in short-term plasticity and a C2 A domain that forms an inhibitory homodimer...

Programmed cell death 1 ligand 2 (PD-L2), a member of the B7 immune checkpoint protein family, emerges as a crucial player in immune modulation. Despite its functional overlap with programmed cell death 1 ligand 1 (PD-L1) in binding to the programmed cell death protein 1 (PD-1) on T cells, PD-L2 exhibits a divergent expression pattern and a higher affinity for PD-1. However, the regulatory mechanisms of PD-L2 remain under-explored. Here, our investigations illustrate the pivotal role of cholesterol in modulating PD-L2 stability...

Small heat shock proteins (sHSPs) are ATP-independent chaperones vital to cellular proteostasis, preventing protein aggregation events linked to various human diseases including cataract. The α-crystallins, αA-crystallin (αAc) and αB-crystallin (αBc), represent archetypal sHSPs that exhibit complex polydispersed oligomeric assemblies and rapid subunit exchange dynamics. Yet, our understanding of how this plasticity contributes to chaperone function remains poorly understood. Using biochemical and biophysical analyses combined with single-particle electron microscopy (EM), we examined structural changes in αAc, αBc and native heteromeric lens α-crystallins (αLc) in their apo-states and at varying degree of chaperone saturation leading to co-aggregation, using lysozyme and insulin as model clients...

No abstract text is available yet for this article.