Publications by authors named "Andrei N Lupas"

Article Synopsis
  • - Many bacteria have protective polysaccharide capsules made of long glycan chains, which can be free or attached to their outer membrane; the group 4 capsule in E. coli is produced by a specific gene operon.
  • - The GfcD protein, part of this operon, is believed to function as a channel for exporting lipid-anchored polysaccharide chains and has two predicted β-barrel domains that could serve as a lateral exit gate.
  • - A study using molecular dynamics showed that while the lateral aperture of GfcD remains stable, lipids do not enter the barrel, but lipid A successfully exits into the membrane, indicating how the capsule is exported.
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  • Histones are crucial for organizing DNA and regulating gene expression, forming different structures in eukaryotes (octamers in nucleosomes) and archaea (dimers in hypernucleosomes).
  • The study focuses on a bacterial histone called HBb, which is vital for the survival of Bdellovibrio bacteriovorus and shows unique characteristics in DNA binding compared to eukaryotic and archaeal histones.
  • HBb is capable of bending and compacting DNA in a way that is not dependent on specific sequences, indicating that bacterial histones share some similarities with, but also differ significantly from, histones in other life forms.
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In protein design, the energy associated with a huge number of sequence-conformer perturbations has to be routinely estimated. Hence, enhancing the throughput and accuracy of these energy calculations can profoundly improve design success rates and enable tackling more complex design problems. In this work, we explore the possibility of tensorizing the energy calculations and apply them in a protein design framework.

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Coiled coils are a widespread and well understood protein fold. Their short and simple repeats underpin considerable structural and functional diversity. The vast majority of coiled coils consist of 7-residue (heptad) sequence repeats, but in essence most combinations of 3- and 4-residue segments, each starting with a residue of the hydrophobic core, are compatible with coiled-coil structure.

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  • Cell immobilization is a technique to enhance the effectiveness of whole-cell biocatalysts, and the researchers previously developed a method using AtaA, a sticky protein from a specific bacterium.
  • Due to challenges in expressing the large AtaA protein, the study focused on creating a smaller version called mini-AtaA, which was easier to express and maintain its adhesion properties.
  • The mini-AtaA showed a higher immobilization ratio on a support material compared to the full-length version, facilitating its use in repetitive enzymatic reactions without negatively impacting cell growth or enzyme activity.
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  • DivIVA, GpsB, FilP, and Scy play key roles in bacterial cell division and interact with each other, but their exact molecular functions are still not well understood.
  • Despite variations across different bacteria, they share a conserved N-terminal sequence motif linked to an evolutionary origin, which we define as the DivIVA-like domain.
  • Our research identifies a new family of proteins that have multiple copies of this domain, suggesting a different structural assembly and potential new functions in the cell division process.
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β-Propellers are toroidal folds, in which consecutive supersecondary structure units of four anti-parallel β-strands-called blades-are arranged radially around a central axis. Uniquely among toroidal folds, blades span the full range of sequence symmetry, from near identity to complete divergence, indicating an ongoing process of amplification and differentiation. We have proposed that the major lineages of β-propellers arose through this mechanism and that therefore their last common ancestor was a single blade, not a fully formed β-propeller.

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  • Protein therapeutics often deal with issues like complex production, instability, poor solubility, and aggregation, which can hinder their effectiveness.
  • The study introduces a topological refactoring strategy to redesign granulopoietic proteins based on the structure of G-CSF, resulting in two high-activity proteins that are both stable and resistant to proteases.
  • These engineered proteins, while different in sequence and structure from native G-CSF, successfully induce the differentiation of human stem cells into neutrophils and demonstrate strong activity in live models, showcasing the versatility of the refactoring approach for various protein targets.
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  • - The SLC5/STAC histidine kinases are a new group of sensor proteins involved in two-component signal transduction systems (TCSTS), linking a signaling domain with an SLC5 solute symporter domain specifically through a STAC domain.
  • - Researchers characterized two TCSTS systems in the Alphaproteobacterium NGR234: one is a CrbS/R homolog crucial for acetate growth, while the other, RpuS/R, is necessary for optimal growth on pyruvate and enhances the expression of a symporter gene when using pyruvate.
  • - Mutants lacking these TCSTS showed reduced nodulation capabilities, producing fewer nodules and at a slower rate compared to the normal strain, highlighting
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Proteins are central to all of the processes of life. For their activity, they almost invariably need to interact with other macromolecules, be they nucleic acids, membranes, glycans, or other proteins. The interaction between proteins is indeed the most common mode of macromolecular interaction underpinning living systems.

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  • - The authors of CASP14 target structures emphasize the biological importance and specific features of selected proteins, assessing how well prediction models matched these features.
  • - This year's CASP demonstrated a significant advancement in accurately predicting protein structures, even for challenging targets.
  • - For the first time, experimentalists acknowledged that computational models not only reproduced key structural elements but could also guide future research on proteins' biological properties.
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Critical assessment of structure prediction (CASP) conducts community experiments to determine the state of the art in computing protein structure from amino acid sequence. The process relies on the experimental community providing information about not yet public or about to be solved structures, for use as targets. For some targets, the experimental structure is not solved in time for use in CASP.

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The assessment of CASP models for utility in molecular replacement is a measure of their use in a valuable real-world application. In CASP7, the metric for molecular replacement assessment involved full likelihood-based molecular replacement searches; however, this restricted the assessable targets to crystal structures with only one copy of the target in the asymmetric unit, and to those where the search found the correct pose. In CASP10, full molecular replacement searches were replaced by likelihood-based rigid-body refinement of models superimposed on the target using the LGA algorithm, with the metric being the refined log-likelihood-gain (LLG) score.

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Outer-membrane beta barrels (OMBBs) are found in the outer membrane of gram-negative bacteria and eukaryotic organelles. OMBBs fold as antiparallel β-sheets that close onto themselves, forming pores that traverse the membrane. Currently known structures include only one barrel, of 8 to 36 strands, per chain.

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Motivation: The proteasome is the main proteolytic machine for targeted protein degradation in archaea and eukaryotes. While some bacteria also possess the proteasome, most of them contain a simpler and more specialized homolog, the heat shock locus V protease. In recent years, three further homologs of the proteasome core subunits have been characterized in prokaryotes: Anbu, BPH and connectase.

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Article Synopsis
  • - The use of advanced deep-learning techniques in protein modeling has significantly raised the standards for high accuracy in the latest CASP14 competition.
  • - We assessed the performance of various groups based on their model submissions, with a focus on AlphaFold2's effectiveness as a molecular replacement tool using a new metric called DipDiff for evaluating improvements in backbone geometry.
  • - Despite AlphaFold2 achieving high accuracy, the second-best method in CASP14 showed notable improvement over the top method from CASP13, highlighting the importance of community collaboration in advancing protein structure prediction techniques.
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  • * The challenge of predicting how proteins fold, known as the protein folding problem, has persisted for decades and was assessed through biennial CASP experiments beginning in 1994.
  • * At CASP14, DeepMind's AlphaFold2 achieved remarkable success in predicting protein structures, leading to a consensus that the structure prediction problem for single protein chains has been largely resolved, with significant implications for the life sciences.
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  • Sequence-specific protein ligations allow for the production of customized proteins using various chemical and enzymatic methods, particularly ligase enzymes, which face limitations like low efficiency and specificity.
  • The newly identified Connectase ligase, derived from archaea, shows improved characteristics by effectively binding to methyltransferase A (MtrA) using a short sequence with a conserved KDPGA motif.
  • Connectase demonstrates significantly higher catalytic rates and yields for ligating two unrelated proteins without side reactions, making it a promising tool for various applications, such as selectively labeled proteins for NMR, protein attachment for cryo-electron microscopy, and multispecific antibody generation.
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  • β-Propellers are diverse structures across all life forms and play key roles as scaffolds in cellular interactions and catalysis, originating from an ancient 'blade' peptide.
  • Recent analyses show that VCBS-like β-propellers form a distinct supercluster related to integrin-like β-propellers and tachylectins, separate from WD40 and Asp-box superclusters.
  • This study enhances the understanding of β-propeller classification by revealing new relationships among different superclusters, utilizing data from expanded sequence databases.
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Computational protein design is rapidly becoming more powerful, and improving the accuracy of computational methods would greatly streamline protein engineering by eliminating the need for empirical optimization in the laboratory. In this work, we set out to design novel granulopoietic agents using a rescaffolding strategy with the goal of achieving simpler and more stable proteins. All of the 4 experimentally tested designs were folded, monomeric, and stable, while the 2 determined structures agreed with the design models within less than 2.

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  • The MPI Bioinformatics Toolkit offers interactive access to various top bioinformatics tools and databases, notably including advanced protein sequence comparison methods like HHblits and HHpred.
  • It comprises 35 tools focused on tasks such as sequence similarity searching, sequence feature prediction, and classification, making it valuable for biomedical research and education in protein sequence analysis.
  • The article highlights how to effectively use the Toolkit's most popular tools, particularly HHpred for homolog detection and structure prediction, along with CLANS for visualizing relationships in large sequence datasets.
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Background: The huntingtin-associated protein 40 (HAP40) abundantly interacts with huntingtin (HTT), the protein that is altered in Huntington's disease (HD). Therefore, we analysed the evolution of HAP40 and its interaction with HTT.

Results: We found that in amniotes HAP40 is encoded by a single-exon gene, whereas in all other organisms it is expressed from multi-exon genes.

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Like pathogens, beneficial endophytic fungi secrete effector proteins to promote plant colonization, for example, through perturbation of host immunity. The genome of the root endophyte Serendipita indica encodes a novel family of highly similar, small alanine- and histidine-rich proteins, whose functions remain unknown. Members of this protein family carry an N-terminal signal peptide and a conserved C-terminal DELD motif.

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Intracellular trafficking depends on the function of Rab GTPases, whose activation is regulated by guanine exchange factors (GEFs). The Rab5 GEF, Rabex5, was previously proposed to be auto-inhibited by its C-terminus. Here, we studied full-length Rabex5 and Rabaptin5 proteins as well as domain deletion Rabex5 mutants using hydrogen deuterium exchange mass spectrometry.

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