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At least 1,171 records · Page 65
All sourcesNASA NTRSDOE OSTI
DOE OSTI2022

A deep dilated convolutional residual network for predicting interchain contacts of protein homodimers

Abstract Motivation Deep learning has revolutionized protein tertiary structure prediction recently. The cutting-edge deep learning methods such as AlphaFold can predict high-accuracy tertiary structures for most individual protein chains. However, the accuracy of predicting quaternary structures of protein complexes consisting of multiple chains is still relatively low due to lack of advanced deep learning methods in the field. Because interchain residue–residue contacts can be used as distance restraints to guide quaternary structure modeling, here we develop a deep dilated convolutional residual network method (DRCon) to predict interchain residue–residue contacts in homodimers from residue–residue co-evolutionary signals derived from multiple sequence alignments of monomers, intrachain residue–residue contacts of monomers extracted from true/predicted tertiary structures or predicted by deep learning, and other sequence and structural features. Results Tested on three homodimer test datasets (Homo_std dataset, DeepHomo dataset and CASP-CAPRI dataset), the precision of DRCon for top L/5 interchain contact predictions (L: length of monomer in a homodimer) is 43.46%, 47.10% and 33.50% respectively at 6 Å contact threshold, which is substantially better than DeepHomo and DNCON2_inter and similar to Glinter. Moreover, our experiments demonstrate that using predicted tertiary structure or intrachain contacts of monomers in the unbound state as input, DRCon still performs well, even though its accuracy is lower than using true tertiary structures in the bound state are used as input. Finally, our case study shows that good interchain contact predictions can be used to build high-accuracy quaternary structure models of homodimers. Availability and implementation The source code of DRCon is available at https://github.com/jianlin-cheng/DRCon. The datasets are available at https://zenodo.org/record/5998532#.YgF70vXMKsB. Supplementary information Supplementary data are available at Bioinformatics online.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2022

OpenMDlr: parallel, open-source tools for general protein structure modeling and refinement from pairwise distances

Easy-to-use, open-source, general-purpose programs for modeling a protein structure from inter-atomic distances are needed for modeling from experimental data and refinement of predicted protein structures. OpenMDlr is an open-source Python package for modeling protein structures from pairwise distances between any atoms, and optionally, dihedral angles. Finally, we provide a user-friendly input format for harnessing modern biomolecular force fields in an easy-to-install package that can efficiently make use of multiple compute cores.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

A roadmap for the functional annotation of protein families: a community perspective

Over the last 25 years, biology has entered the genomic era and is becoming a science of ‘big data’. Most interpretations of genomic analyses rely on accurate functional annotations of the proteins encoded by more than 500 000 genomes sequenced to date. By different estimates, only half the predicted sequenced proteins carry an accurate functional annotation, and this percentage varies drastically between different organismal lineages. Such a large gap in knowledge hampers all aspects of biological enterprise and, thereby, is standing in the way of genomic biology reaching its full potential. A brainstorming meeting to address this issue funded by the National Science Foundation was held during 3–4 February 2022. Bringing together data scientists, biocurators, computational biologists and experimentalists within the same venue allowed for a comprehensive assessment of the current state of functional annotations of protein families. Further, major issues that were obstructing the field were identified and discussed, which ultimately allowed for the proposal of solutions on how to move forward.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Diversity and conservation of plant small secreted proteins associated with arbuscular mycorrhizal symbiosis

Arbuscular mycorrhizal symbiosis (AMS) is widespread mutualistic association between plants and fungi, which plays an essential role in nutrient exchange, enhancement in plant stress resistance, development of host, and ecosystem sustainability. Previous studies have shown that plant small secreted proteins (SSPs) are involved in beneficial symbiotic interactions. However, the role of SSPs in the evolution of AMS has not been well studied yet. In this study, we performed computational analysis of SSPs in 60 plant species and identified three AMS-specific ortholog groups containing SSPs only from at least 30% of the AMS species in this study and three AMS-preferential ortholog groups containing SSPs from both AMS and non-AMS species, with AMS species containing significantly more SSPs than non-AMS species. We found that independent lineages of monocot and eudicot plants contained genes in the AMS-specific ortholog groups and had significant expansion in the AMS-preferential ortholog groups. Also, two AMS-preferential ortholog groups showed convergent changes, between monocot and eudicot species, in gene expression in response to arbuscular mycorrhizal fungus Rhizophagus irregularis. Furthermore, conserved cis-elements were identified in the promoter regions of the genes showing convergent gene expression. We found that the SSPs, and their closely related homologs, in each of three AMS-preferential ortholog groups, had some local variations in the protein structural alignment. We also identified genes co-expressed with the Populus trichocarpa SSP genes in the AMS-preferential ortholog groups. This first plant kingdom-wide analysis on SSP provides insights on plant-AMS convergent evolution with specific SSP gene expression and local diversification of protein structures.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

A small secreted protein serves as a plant-derived effector mediating symbiosis between Populus and Laccaria bicolor

Beneficial symbiotic fungi colonize plant tissues, delivering crucial ecosystem services such as carbon sequestration and plant fertilization. Specifically, trees that form a nutrient-acquiring symbiosis with mutualistic ectomycorrhizal (ECM) fungi gain advantages from these associations by experiencing enhanced growth rates and increased resilience to both biotic and abiotic stresses. Despite the vital role ECM fungi play in the nutrition and well-being of trees, identifying key regulators participating in the molecular communication between plant and fungal cells is still in its early stages. The mutualistic relationship between Laccaria bicolor and Populus spp. has been utilized as a model system for investigating ECM symbiosis at the molecular level. It has been demonstrated that the fungus L. bicolor secretes Mycorrhiza-induced Small Secreted Proteins (MiSSPs) required for ECM development. Meanwhile, we have previously shown that P. trichocarpa small, secreted proteins (PtSSPs) are highly induced during mutualistic symbiosis and some of them can enter, via in-vitro feeding, L. bicolor hyphae affecting their growth and morphology. However, the exact role and mode of action of PtSSPs in mutualistic symbiosis remain unknown. Because previous study showed that PtSSP1 is taking up by fungal cell and then localize in fungal cells, we decide to dig further on its putative role in fungal cells and also by overexpressing it in poplar because it is not technically possible yet to overexpress poplar protein in Laccaria bicolor hyphae. Here, we further characterized the function of PtSSP1(Potri.009G063200) in ectomycorrhization, which accumulates in the nucleus of L. bicolor in an in-vitro feeding experiment. Our results provide new knowledge for the genetic engineering of plants to control associated microbes.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Identification and characterization of the WYL BrxR protein and its gene as separable regulatory elements of a BREX phage restriction system

Bacteriophage exclusion (‘BREX’) phage restriction systems are found in a wide range of bacteria. Various BREX systems encode unique combinations of proteins that usually include a site-specific methyltransferase; none appear to contain a nuclease. Here we describe the identification and characterization of a Type I BREX system from Acinetobacter and the effect of deleting each BREX ORF on growth, methylation, and restriction. We identified a previously uncharacterized gene in the BREX operon that is dispensable for methylation but involved in restriction. Biochemical and crystallographic analyses of this factor, which we term BrxR (‘BREX Regulator’), demonstrate that it forms a homodimer and specifically binds a DNA target site upstream of its transcription start site. Deletion of the BrxR gene causes cell toxicity, reduces restriction, and significantly increases the expression of BrxC. In contrast, the introduction of a premature stop codon into the BrxR gene, or a point mutation blocking its DNA binding ability, has little effect on restriction, implying that the BrxR coding sequence and BrxR protein play independent functional roles. We speculate that elements within the BrxR coding sequence are involved in cis regulation of anti-phage activity, while the BrxR protein itself plays an additional regulatory role, perhaps during horizontal transfer.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Structural and functional insights into the interaction between the bacteriophage T4 DNA processing proteins gp32 and Dda

Abstract Bacteriophage T4 is a classic model system for studying the mechanisms of DNA processing. A key protein in T4 DNA processing is the gp32 single-stranded DNA-binding protein. gp32 has two key functions: it binds cooperatively to single-stranded DNA (ssDNA) to protect it from nucleases and remove regions of secondary structure, and it recruits proteins to initiate DNA processes including replication and repair. Dda is a T4 helicase recruited by gp32, and we purified and crystallized a gp32–Dda–ssDNA complex. The low-resolution structure revealed how the C-terminus of gp32 engages Dda. Analytical ultracentrifugation analyses were consistent with the crystal structure. An optimal Dda binding peptide from the gp32 C-terminus was identified using surface plasmon resonance. The crystal structure of the Dda–peptide complex was consistent with the corresponding interaction in the gp32–Dda–ssDNA structure. A Dda-dependent DNA unwinding assay supported the structural conclusions and confirmed that the bound gp32 sequesters the ssDNA generated by Dda. The structure of the gp32–Dda–ssDNA complex, together with the known structure of the gp32 body, reveals the entire ssDNA binding surface of gp32. gp32–Dda–ssDNA complexes in the crystal are connected by the N-terminal region of one gp32 binding to an adjacent gp32, and this provides key insights into this interaction.

Biochemistry & Molecular Biology↗
DOE OSTI2022

A mini-TGA protein modulates gene expression through heterogeneous association with transcription factors

Abstract TGA (TGACG-binding) transcription factors, which bind their target DNA through a conserved basic region leucine zipper (bZIP) domain, are vital regulators of gene expression in salicylic acid (SA)-mediated plant immunity. Here, we investigated the role of StTGA2.1, a potato (Solanum tuberosum) TGA lacking the full bZIP, which we named a mini-TGA. Such truncated proteins have been widely assigned as loss-of-function mutants. We, however, confirmed that StTGA2.1 overexpression compensates for SA-deficiency, indicating a distinct mechanism of action compared with model plant species. To understand the underlying mechanisms, we showed that StTGA2.1 can physically interact with StTGA2.2 and StTGA2.3, while its interaction with DNA was not detected. We investigated the changes in transcriptional regulation due to StTGA2.1 overexpression, identifying direct and indirect target genes. Using in planta transactivation assays, we confirmed that StTGA2.1 interacts with StTGA2.3 to activate StPRX07, a member of class III peroxidases (StPRX), which are known to play role in immune response. Finally, via structural modeling and molecular dynamics simulations, we hypothesized that the compact molecular architecture of StTGA2.1 distorts DNA conformation upon heterodimer binding to enable transcriptional activation. This study demonstrates how protein truncation can lead to distinct functions and that such events should be studied carefully in other protein families.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

N-Terminal domain homologs of the orange carotenoid protein increase quenching of cyanobacterial phycobilisomes

Stress exerted by excess captured light energy in cyanobacteria is prevented by the photoprotective activity of the orange carotenoid protein (OCP). Under high light, the OCP converts from an orange, inactive form (OCP O ) into the red form (OCP R ) that binds to and quenches the phycobilisome (PBS). Structurally, the OCP consists of 2 domains: the N-terminal effector domain and a C-terminal regulatory domain. Structural analysis of the OCP-PBS complex showed that the N-terminal domains of an OCP dimer interact with the PBS core. These N-terminal OCP domains have single-domain protein paralogs known as helical carotenoid proteins (HCPs). Using PBS quenching assays, we show that the HCP4 and HCP5 homologs efficiently quench PBS fluorescence in vitro, surpassing the quenching ability of the OCP. This is consistent with computational quantum mechanics/molecular mechanics results. Interestingly, when using a maximum quenching concentration of OCP with PBSs, HCP5 addition further increases PBS quenching. Our results provide mechanistic insight into the quenching capacity and roles of HCP4 and HCP5 in cyanobacteria, suggesting that they are more than simply functionally redundant to the OCP.

Sheppard, Damien I.↗
DOE OSTI2026

The small protein SbtC is a functional component of the CO 2 concentrating mechanism in Synechocystis sp. PCC 6803

Oxygenic phototrophs fix CO 2 via the enzyme ribulose-1,5-bisphosphate carboxylase/oxygenase (RubisCO), which shows relatively low CO 2 affinity and specificity. To circumvent low and fluctuating CO 2 concentrations in aquatic systems, cyanobacteria and algae have evolved sophisticated inorganic carbon (Ci) concentrating mechanisms (CCMs). Bicarbonate transporters such as SbtA play a crucial role in the cyanobacterial CCM and hence display multiple layers of tight regulation. Control of sbtA gene expression and corresponding transporter activity involves the PII-like protein SbtB, whose gene is frequently co-transcribed with sbtA. A previously non-annotated gene located upstream of the sbtAB operon in the model Synechocystis sp. PCC 6803 encodes the small protein SbtC, composed of 80 amino acids. Presence of SbtC was confirmed by immunoblotting of the sbtC-coding sequence fused to a Flag-tag. Similar to sbtAB , transcription of the sbtC locus is induced by low CO 2 availability; however, it is controlled independently. Mutation of the sbtC locus in a wild-type background produced only a mild phenotype, even under low CO 2 , but impaired diurnal growth resembled that of the mutant ΔsbtB . Biochemical analysis indicated a trimeric SbtABC complex in the membrane. Bicarbonate leakage from cells was strongly elevated when either sbtB or sbtC was deleted from recombinant Synechocystis strains harboring only SbtA as single Ci uptake system. Here, our results provide evidence that SbtC contributes to the formation of the SbtAB complex, thereby regulating bicarbonate exchange at the cytoplasmic membrane. Well-conserved SbtC-like proteins encoded in the neighborhood of sbtAB exist in many cyanobacterial genomes, pointing toward an important role in the cyanobacterial CCM.

Walke, Peter [Univ. of Rostock (Germany)] (ORCID:0↗
DOE OSTI2024

A Sorghum F-Box Protein Induces an Oxidative Burst in the Defense Against Colletotrichum sublineola

The hemibiotrophic fungal pathogen Colletotrichum sublineola is the causal agent of anthracnose in sorghum ( Sorghum bicolor), resulting in leaf blight, stalk rot, and head blight in susceptible genotypes, with yield losses of up to 50%. The development of anthracnose-resistant cultivars can reduce reliance on fungicides and provide a more sustainable and economical means for disease management. A previous genome-wide association study of the sorghum association panel identified the candidate resistance gene Sobic.005G172300 encoding an F-box protein. To better understand the role of this gene in the defense against C. sublineola, gene expression following infection with C. sublineola was monitored by RNA sequencing in seedlings of sorghum accession SC110, which harbored the resistance allele, and three accessions that harbored a susceptible allele. Only in SC110 did the expression of Sobic.005G172300 increase during the biotrophic phase of infection. Subsequent transcriptome analysis, gene co-expression networks, and gene regulatory networks of inoculated and mock-inoculated seedlings of resistant and susceptible accessions suggest that the increase in expression of Sobic.005G172300 induces an oxidative burst by lowering the concentration of ascorbic acid during the biotrophic phase of infection. Based on gene regulatory network analysis, the protein encoded by Sobic.005G172300 is proposed to target proteins involved in the biosynthesis of ascorbic acid for polyubiquitination through the SCF E3 ubiquitin ligase, causing their degradation via the proteasome.

Plant Sciences↗
DOE OSTI2020

HIV influences microtubule associated protein-2: potential marker of HIV-associated neurocognitive disorders

Postmortem brains of patients diagnosed with HIV-1-associated neurocognitive disorders (HAND) exhibit loss of dendrites. However, the mechanisms by which synapses are damaged are not fully understood. Dendrite length and remodeling occurs via microtubules, the dynamics of which are regulated by microtubule-binding proteins, including microtubule-associated protein 2 (MAP2). The HIV protein gp120 is neurotoxic and interferes with neuronal microtubules. We measured MAP2 concentrations in human cerebrospinal fluid (CSF) and MAP2 immunoreactivity in rat cortical neurons exposed to HIV and gp120. First, we examined whether HIV affects MAP2 levels by analyzing the CSF of 27 persons living with HIV (PLH) whose neurocognitive performance had been characterized. We then used rat cortical neurons to study the mechanisms of HIV-mediated dendritic loss. PLH who had HAND had greater MAP2 concentrations within the CSF than cognitive normal PLH. In cortical neurons, the deleterious effect of HIV on MAP2-positive dendrites occurred through a gp120-mediated mechanism. The neurotoxic effect of HIV was blocked by a CCR5 antagonist and prevented by Helix-A, a peptide that displaces gp120 from binding to microtubules, conjugated to a nanolipoprotein particle delivery platform. Our findings support that HIV at least partially effects its neurotoxicity via neuronal cytoskeleton modifications and provide evidence of a new therapeutic compound that could be used to prevent the HIV-associated neuropathology.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

Cryo-EM structure of a methanogen nitrogenase-PII protein supercomplex

Abstract Nitrogenases are metalloenzymes that catalyze the reduction of atmospheric dinitrogen to ammonia, sustaining the global nitrogen cycle. While bacterial nitrogenase has been extensively characterized, the architecture and regulation of archaeal nitrogenases remain unknown despite longstanding evidence of nitrogen fixation in methanogens. Here we report a 3.1 Å cryo-electron microscopy structure of a native nitrogenase–PII protein supercomplex from Methanosarcina acetivorans. The structure reveals an unprecedented assembly of three NifDK heterotetramers bridged by six NifI1,2 heterotrimeric PII complexes, which sterically block NifH association and lock the enzyme in an inactive state. The NifI complexes display asymmetric binding of ADP and 2-oxoglutarate, coupling nitrogenase inhibition directly to cellular energy and nitrogen status. Addition of 2-oxoglutarate and ATP releases the NifI complexes, stimulating a threefold increase in NifDK activity in vitro. This higher-order architecture uncovers a previously unrecognized regulatory strategy in methanogens, in which PII proteins drive nitrogenase oligomerization to control activity. The discovery that nitrogenase activity may be modulated through direct assembly into higher-order structures opens new avenues for exploring nitrogenase evolution, regulation, and biotechnological applications. One sentence summary Discovery of a nitrogenase-PII protein supercomplex in methanogens, uncovering a metabolite-gated assembly mechanism for nitrogenase inhibition.

Nitrogenase, Electron Transfer, Methanogen↗
DOE OSTI2024

BRAKER3: Fully automated genome annotation using RNA-seq and protein evidence with GeneMark-ETP, AUGUSTUS, and TSEBRA

Gene prediction has remained an active area of bioinformatics research for a long time. Still, gene prediction in large eukaryotic genomes presents a challenge that must be addressed by new algorithms. The amount and significance of the evidence available from transcriptomes and proteomes vary across genomes, between genes, and even along a single gene. User-friendly and accurate annotation pipelines that can cope with such data heterogeneity are needed. The previously developed annotation pipelines BRAKER1 and BRAKER2 use RNA-seq or protein data, respectively, but not both. A further significant performance improvement integrating all three data types was made by the recently released GeneMark-ETP. We here present the BRAKER3 pipeline that builds on GeneMark-ETP and AUGUSTUS, and further improves accuracy using the TSEBRA combiner. BRAKER3 annotates protein-coding genes in eukaryotic genomes using both short-read RNA-seq and a large protein database, along with statistical models learned iteratively and specifically for the target genome. We benchmarked the new pipeline on genomes of 11 species under an assumed level of relatedness of the target species proteome to available proteomes. BRAKER3 outperforms BRAKER1 and BRAKER2. The average transcript-level F1-score is increased by about 20 percentage points on average, whereas the difference is most pronounced for species with large and complex genomes. BRAKER3 also outperforms other existing tools, MAKER2, Funannotate, and FINDER. The code of BRAKER3 is available on GitHub and as a ready-to-run Docker container for execution with Docker or Singularity. Overall, BRAKER3 is an accurate, easy-to-use tool for eukaryotic genome annotation.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Overall protein structure quality assessment using hydrogen-bonding parameters

Atomic model refinement at low resolution is often a challenging task. This is mostly because the experimental data are not sufficiently detailed to be described by atomic models. To make refinement practical and ensure that a refined atomic model is geometrically meaningful, additional information needs to be used such as restraints on Ramachandran plot distributions or residue side-chain rotameric states. However, using Ramachandran plots or rotameric states as refinement targets diminishes the validating power of these tools. Therefore, finding additional model-validation criteria that are not used or are difficult to use as refinement goals is desirable. Hydrogen bonds are one of the important noncovalent interactions that shape and maintain protein structure. These interactions can be characterized by a specific geometry of hydrogen donor and acceptor atoms. Systematic analysis of these geometries performed for quality-filtered high-resolution models of proteins from the Protein Data Bank shows that they have a distinct and a conserved distribution. Here, it is demonstrated how this information can be used for atomic model validation.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Proteome-scale Deployment of Protein Structure Prediction Workflows on the Summit Supercomputer

Deep learning has contributed to major advances in the prediction of protein structure from sequence, a fundamental problem in structural bioinformatics. With predictions now approaching the accuracy of crystallographic experiments, and with accelerators like GPUs and TPUs making inference using large models rapid, genome-level structure prediction becomes an obvious aim. Leadership-class computing resources can be used to perform genome-scale protein structure prediction using state-of-the-art deep learning models, providing a wealth of new data for systems biology applications. Here we describe our efforts to efficiently deploy the AlphaFold v.2 program, for full-proteome structure prediction, at scale on the Oak Ridge Leadership Computing Facility's resources, including the Summit supercomputer. We performed inference to produce the predicted structures for 40,526 protein sequences, corresponding to four prokaryotic proteomes and one plant proteome, using under 4,400 total Summit node hours, equivalent to using the majority of the supercomputer for a little over one hour. We also designed an optimized structure refinement that reduced the time for the relaxation stage of the AlphaFold pipeline by over 10X for longer sequences. We demonstrate the types of analyses that can be performed on proteome-scale collections of sequences, including a search for novel quaternary structures and implications for functional annotation.

Gao, Mu↗
DOE OSTI2021

Capturing an elusive but critical element: Natural protein enables actinium chemistry

Actinium-based therapies could revolutionize cancer medicine but remain tantalizing due to the difficulties in studying and limited knowledge of Ac chemistry. Current efforts focus on small synthetic chelators, limiting radioisotope complexation and purification efficiencies. Here, we demonstrate a straightforward strategy to purify medically relevant radiometals, actinium(III) and yttrium(III), and probe their chemistry, using the recently discovered protein, lanmodulin. The stoichiometry, solution behavior, and formation constant of the 228 Ac 3+ -lanmodulin complex and its 90 Y 3+ / nat Y 3+ / nat La 3+ analogs were experimentally determined, representing the first actinium-protein and strongest actinide(III)-protein complex (sub-picomolar Kd) to be characterized. Lanmodulin’s unparalleled properties enable the facile purification recovery of radiometals, even in the presence of >10 +10 equivalents of competing ions and at ultratrace levels: down to 2 femtograms 90 Y 3+ and 40 attograms 228 Ac 3+ . The lanmodulin-based approach charts a new course to study elusive isotopes and develop versatile chelating platforms for medical radiometals, both for high-value separations and potential in vivo applications.

38 RADIATION CHEMISTRY, RADIOCHEMISTRY, AND NUCLEA↗
DOE OSTI2023

Human cerebrospinal fluid contains diverse lipoprotein subspecies enriched in proteins implicated in central nervous system health

Lipoproteins in cerebrospinal fluid (CSF) of the central nervous system (CNS) resemble plasma high-density lipoproteins (HDLs), which are a compositionally and structurally diverse spectrum of nanoparticles with pleiotropic functionality. Whether CSF lipoproteins (CSF-Lps) exhibit similar heterogeneity is poorly understood because they are present at 100-fold lower concentrations than plasma HDL. To investigate the diversity of CSF-Lps, we developed a sensitive fluorescent technology to characterize lipoprotein subspecies in small volumes of human CSF. We identified 10 distinctly sized populations of CSF-Lps, most of which were larger than plasma HDL. Mass spectrometric analysis identified 303 proteins across the populations, over half of which have not been reported in plasma HDL. Computational analysis revealed that CSF-Lps are enriched in proteins important for wound healing, inflammation, immune response, and both neuron generation and development. Network analysis indicated that different subpopulations of CSF-Lps contain unique combinations of these proteins. Our study demonstrates that CSF-Lp subspecies likely exist that contain compositional signatures related to CNS health.

59 BASIC BIOLOGICAL SCIENCES↗