Evolutionary constraints on structural similarity in orthologs and paralogs

Although a quantitative relationship between sequence similarity and structural similarity has long been established, little is known about the impact of orthology on the relationship between protein sequence and structure. Among homologs, orthologs (derived by speciation) more frequently have similar functions than paralogs (derived by duplication). Here, we hypothesize that an orthologous pair will tend to exhibit greater structural similarity than a paralogous pair at the same level of sequence similarity. To test this hypothesis, we used 284,459 pairwise structure‐based alignments of 12,634 unique domains from SCOP as well as orthology and paralogy assignments from OrthoMCL DB. We divided the comparisons by sequence identity and determined whether the sequence‐structure relationship differed between the orthologs and paralogs. We found that at levels of sequence identity between 30 and 70%, orthologous domain pairs indeed tend to be significantly more structurally similar than paralogous pairs at the same level of sequence identity. An even larger difference is found when comparing ligand binding residues instead of whole domains. These differences between orthologs and paralogs are expected to be useful for selecting template structures in comparative modeling and target proteins in structural genomics.     

Structural alterations in cell organelles induced by photodynamic treatment with chlorin p6-histamine conjugate in human oral carcinoma cells probed by 3D fluorescence microscopy

We have explored the intracellular cell organelle's structural alterations after photodynamic treatment with chlorin p₆-histamine conjugate (Cp₆-his) in human oral cancer cells. Herein, the cells were treated with Cp₆-his (10 μm) and counterstained with organelle-specific fluorescence probes to find the site of intracellular localization using confocal microscopy. For photodynamic therapy (PDT), the cells were exposed to ~30 kJ/m² red light (660 ± 20 nm) to induce ~90% cytotoxicity. We used the three-dimensional (3D) image reconstruction approach to analyze the photodynamic damage to cell organelles. The result showed that Cp₆-his localized mainly in the endoplasmic reticulum (ER) and lysosomes but not in mitochondria and Golgi apparatus (GA). The 3D model revealed that in necrotic cells, PDT led to extensive fragmentation of ER and fragmentation and swelling of GA as well. Results suggest that the indirect damage to GA occurred due to loss of connection between ER and GA. Moreover, in damaged cells with no sign of necrosis, the perinuclear ER appeared condensed and surrounded by several small clumps at the peripheral region of the cell, and the GA was observed to form a single condensed structure. Since these structural changes were associated with apoptotic cell death, it is suggested that the necrotic and apoptotic death induced by PDT with Cp₆-his is determined by the severity of damage to ER and indirect damage to GA. The results suggest that the indirect damage to cell organelle apart from the sites of photosensitizer localization and the severity of damage at the organelle level contribute significantly to the mode of cell death in PDT.     

Polygenic risk scores for alcohol involvement relate to brain structure in substance-naïve children: Results from the ABCD study

Brain imaging-derived structural correlates of alcohol involvement have largely been speculated to arise as a consequence of alcohol exposure. However, they may also reflect predispositional risk. In substance naïve children of European ancestry who completed the baseline session of the Adolescent Brain Cognitive Development (ABCD) Study (n = 3013), mixed-effects models estimated whether polygenic risk scores (PRS) for problematic alcohol use (PAU-PRS) and drinks per week (DPW-PRS) are associated with magnetic resonance imaging-derived brain structure phenotypes (i.e., total and regional: cortical thickness, surface area and volume; subcortical volume; white matter volume, fractional anisotropy, mean diffusivity). Follow-up analyses evaluated whether any identified regions were also associated with polygenic risk among substance naïve children of African ancestry (n = 898). After adjustment for multiple testing correction, polygenic risk for PAU was associated with lower volume of the left frontal pole and greater cortical thickness of the right supramarginal gyrus (|βs| > 0.009; ps < 0.001; ps_fdr < 0.046; r²s < 0.004). PAU PRS and DPW PRS showed nominally significant associations with a host of other regional brain structure phenotypes (e.g., insula surface area and volume). None of these regions showed any, even nominal association among children of African ancestry. Genomic liability to alcohol involvement may manifest as variability in brain structure during middle childhood prior to alcohol use initiation. Broadly, alcohol-related variability in brain morphometry may partially reflect predisposing genomic influence. Larger discovery genome-wide association studies and target samples of diverse ancestries are needed to determine whether observed associations may generalize across ancestral origins.     

Integration of evidence across human and model organism studies: A meeting report

The National Institute on Drug Abuse and Joint Institute for Biological Sciences at the Oak Ridge National Laboratory hosted a meeting attended by a diverse group of scientists with expertise in substance use disorders (SUDs), computational biology, and FAIR (Findability, Accessibility, Interoperability, and Reusability) data sharing. The meeting's objective was to discuss and evaluate better strategies to integrate genetic, epigenetic, and 'omics data across human and model organisms to achieve deeper mechanistic insight into SUDs. Specific topics were to (a) evaluate the current state of substance use genetics and genomics research and fundamental gaps, (b) identify opportunities and challenges of integration and sharing across species and data types, (c) identify current tools and resources for integration of genetic, epigenetic, and phenotypic data, (d) discuss steps and impediment related to data integration, and (e) outline future steps to support more effective collaboration—particularly between animal model research communities and human genetics and clinical research teams. This review summarizes key facets of this catalytic discussion with a focus on new opportunities and gaps in resources and knowledge on SUDs.     

Structure of the 80S ribosome from Saccharomyces cerevisiae--tRNA-ribosome and subunit-subunit interactions.

A cryo-EM reconstruction of the translating yeast 80S ribosome was analyzed. Computationally separated rRNA and protein densities were used for docking of appropriately modified rRNA models and homology models of yeast ribosomal proteins. The core of the ribosome shows a remarkable degree of conservation. However, some significant differences in functionally important regions and dramatic changes in the periphery due to expansion segments and additional ribosomal proteins are evident. As in the bacterial ribosome, bridges between the subunits are mainly formed by RNA contacts. Four new bridges are present at the periphery. The position of the P site tRNA coincides precisely with its prokaryotic counterpart, with mainly rRNA contributing to its molecular environment. This analysis presents an exhaustive inventory of an eukaryotic ribosome at the molecular level.