Top 10 Biorxiv Papers Today in Biochemistry


2.028 Mikeys
#1. Cysteine modification can gate non-equilibrium conformational dynamics during enzyme catalysis
Medhanjali DasGupta, Dominik Budday, Peter Madzelan, Javier Seravalli, Brandon Hayes, Raymond G. Sierra, Roberto Alonso-Mori, Aaron S. Brewster, Nicholas K. Sauter, Gregory A. Applegate, Virendra Tiwari, David B. Berkowitz, Michael C. Thompson, James S. Fraser, Michael E. Wall, Henry van den Bedem, Mark A. Wilson
Post-translational modification of cysteine residues can regulate protein function and is essential for catalysis by cysteine-dependent enzymes. Covalent modifications neutralize charge on the reactive cysteine thiolate anion and thus alter the active site electrostatic environment. Although a vast number of enzymes rely on cysteine modification for function, precisely how altered structural and electrostatic states of cysteine affect protein dynamics remains poorly understood. Here we use X-ray crystallography, computer simulations, and enzyme kinetics to characterize how covalent modification of the active site cysteine residue in isocyanide hydratase (ICH) affects the protein conformational ensemble. ICH exhibits a concerted helical displacement upon cysteine modification that is gated by changes in hydrogen bond strength between the cysteine thiolate and the backbone amide of the highly strained residue Ile152. The mobile helix samples alternative conformations in crystals exposed to synchrotron X-ray radiation due to the...
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LivingMatterLab: Check out this new preprint https://t.co/MauC4zgiPz by Henry, James, and Mark on #enzyme dynamics! https://t.co/QZem9zdIir
HvandenBedem: New preprint https://t.co/X3RiZ6sbwP w/ Mark Wilson & @fraser_lab! We use (serial) X-ray crystallography, computation, and enzyme kinetics to characterize isocyanide hydratase (ICH). ICH samples an extraordinarily wide-spread and well-resolved conformational ensemble in xtals https://t.co/8YRAAtKXcd
fraser_lab: RT @HvandenBedem: New preprint https://t.co/X3RiZ6sbwP w/ Mark Wilson & @fraser_lab! We use (serial) X-ray crystallography, computation, an…
MattChallacombe: RT @HvandenBedem: New preprint https://t.co/X3RiZ6sbwP w/ Mark Wilson & @fraser_lab! We use (serial) X-ray crystallography, computation, an…
Jackson_Lab: RT @HvandenBedem: New preprint https://t.co/X3RiZ6sbwP w/ Mark Wilson & @fraser_lab! We use (serial) X-ray crystallography, computation, an…
_amelie_rocks: RT @HvandenBedem: New preprint https://t.co/X3RiZ6sbwP w/ Mark Wilson & @fraser_lab! We use (serial) X-ray crystallography, computation, an…
DominikBudday: RT @HvandenBedem: New preprint https://t.co/X3RiZ6sbwP w/ Mark Wilson & @fraser_lab! We use (serial) X-ray crystallography, computation, an…
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Authors: 17
Total Words: 11070
Unqiue Words: 3317

1.998 Mikeys
#2. Mechanistic Analyses of Supercoiling Behaviors of DNA in Nucleosomes and Chromatins
Hao Zhang, Tianhu Li
Besides those in 146-base pair nucleosome core particle DNA, supercoils have been known to be present in 10-base pair arm DNA segments and naked linker DNA segments. The interacting patterns among histone octamers, histone H1, 10-base pair arm DNA segments and linker DNA have, however, not yet been elucidated. In the current report, we examine correlations among constituents of nucleosomes from the mechanistic perspectives and present molecular pathways for elucidating supercoiling behaviors of their component DNA sequences. It is our hope that our new analyses could serve as incentives to further clarify correlations between histones and DNA in the dynamic structures of chromatins in the future.
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Authors: 2
Total Words: 8141
Unqiue Words: 1994

1.998 Mikeys
#3. X-ray structures of two active secreted Bacteroides thetaiotaomicron C11 proteases in complex with peptide-based inhibitors
Emily J. Roncase, Gonzalo E. Gonzalez-Paez, Dennis W. Wolan
Commensal bacteria secrete proteins and metabolites to influence host intestinal homeostasis and proteases represent a significant constituent of the components at the host:microbiome interface. Here, we determined the structures of the two secreted C11 cysteine proteases encoded by the established gut commensal Bacteroides thetaiotaomicron . We employed mutational analysis to demonstrate the two proteases, termed thetapain and iotapain, undergo in trans self-maturation after lysine and/or arginine residues, as observed for other C11 proteases. We determined the structures of the active forms of thetapain and iotapain in complex with irreversible peptide inhibitors, Ac-VLTK-AOMK and biotin-VLTK-AOMK, respectively. Structural comparisons revealed key active-site interactions important for peptide recognition are more extensive for thetapain; however, both proteases employ a glutamate residue to preferentially bind small polar residues at the P2 position. Our results will aid in the design of protease-specific probes to ultimately...
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biorxivpreprint: X-ray structures of two active secreted Bacteroides thetaiotaomicron C11 proteases in complex with peptide-based inhibitors https://t.co/8pFxdY58HB #bioRxiv
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Authors: 3
Total Words: 8247
Unqiue Words: 2596

1.997 Mikeys
#4. Compartmentalized Biosynthesis of Mycophenolic Acid
Wei Zhang, Lei Du, Zepeng Qu, Xingwang Zhang, Fengwei Li, Zhong Li, Feifei Qi, Xiao Wang, Yuanyuan Jiang, Ping Men, Jingran Sun, Shaona Cao, Ce Geng, Fengxia Qi, Xiaobo Wan, Changning Liu, Shengying Li
Mycophenolic acid (MPA) from filamentous fungi is the first natural product antibiotic in human history and a first-line immunosuppressive drug for organ transplantations and autoimmune diseases. However, its biosynthetic mechanisms have remained a long-standing mystery. Here, we elucidate the MPA biosynthetic pathway that features both compartmentalized enzymatic steps and unique cooperation between biosynthetic and β-oxidation catabolism machineries based on targeted gene inactivation, feeding experiments in heterologous expression hosts, enzyme functional characterization and kinetic analysis, and microscopic observation of protein subcellular localization. Besides identification of the oxygenase MpaB′ as the long-sought key enzyme responsible for the oxidative cleavage of sesquiterpene side chain, we reveal the intriguing pattern of compartmentalization for the MPA biosynthetic enzymes, including the cytosolic polyketide synthase MpaC' and O-methyltransferase MpaG', the Golgi apparatus-associated prenyltransferase MpaA', the...
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biorxivpreprint: Compartmentalized Biosynthesis of Mycophenolic Acid https://t.co/0EYYhfZio1 #bioRxiv
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Authors: 17
Total Words: 6257
Unqiue Words: 2442

1.996 Mikeys
#5. Integrin cytoplasmic domain and pITAM compete for spleen tyrosine kinase binding
Lina Antenucci, Maarit Hellman, Vesa P. Hytonen, Perttu Permi, Jari Ylanne
In hematopoietic tissues cell-cell communication involves immunoreceptors and specialized cell adhesion receptors that both mediate intracellular signals. Spleen tyrosine kinase (Syk) is a non-receptor tyrosine kinase involved in the downstream signaling of both immunoreceptors tyrosine activation motif (ITAM) receptors and integrin family cell adhesion receptors. Both phosphorylated ITAM (pITAM) and integrins bind to the regulatory domain of Syk composed of two Src homology 2 (SH2) domains. The interaction with pITAM is mediated by binding of a specific phosphotyrosine to each of the SH2 domains, leading to conformational changes and Syk kinase activation. Integrins bind to the interdomain A segment between the two SH2 domains and to the N-terminal SH2 domain, but the detailed binding site is not known. In order to map the binding site, we performed NMR titration experiments. We found that integrin cytoplasmic domain peptide induced chemical shift changes near the IA segment and at the phosphotyrosine binding site of the...
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Authors: 5
Total Words: 6118
Unqiue Words: 1881

0.0 Mikeys
#6. In vitro and in silico identification of the mechanism of interaction of antimalarial drug - artemisinin with human serum albumin and genomic DNA
Siranush Ginosyan, Hovakim Grabski, Susanna Tiratsuyan
Artemisinins are secondary metabolites of the medicinal plant Artemisia annua, which has been traditionally used in Chinese medicine. Artemisinins have anti-inflammatory, anticarcinogenic, immunomodulatory, antimicrobial, anthelmintic, antiviral, antioxidant, and other properties. Our preliminary reverse virtual screening demonstrated that the ligand-binding domain of the human glucocorticoid receptor (LBD of hGR) is the optimal target for artemisinin. At the same time, the binding sites for artemisinin with the ligand-binding domain of the human glucocorticoid receptor coincide with those of dexamethasone. However, the pharmacokinetics, pharmacodynamics, and exact molecular targets and mechanisms of action of artemisinin are not well known. In this work, the interaction of artemisinin with human serum albumin (HSA) was studied both in vitro and in silico. The results indicate that artemisinin leads to a decrease in optical absorption and quenching of fluorescence by a static mechanism, which is similar to the effect of...
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h_grabski: In vitro and in silico identification of the mechanism of interaction of antimalarial drug - artemisinin with human serum albumin and genomic DNA https://t.co/CBnZ2FzK9N
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Authors: 3
Total Words: 9004
Unqiue Words: 2896

0.0 Mikeys
#7. Systematic Development Of Sandwich Immunoassays For The Plasma Secretome
Ragna S Haeussler, Annika Bendes, MariaJesus Iglesias, Laura Sanchez-Rivera, Tea Dodig-Crnkovic, Sanna Bystrom, Claudia Fredolini, Elin Birgersson, Matilda Dale, Fredrik Edfors, Linn Fagerberg, Johan Rockberg, Hanna Tegel, Mathias Uhlen, Ulrika Qundos, Jochen M Schwenk
The plasma proteome offers a clinically useful window into human health and disease. With recent progress made on the development of highly multiplexed immunoassays with high sample throughput, a remaining need is to establish a pipeline for validating the individual proteins that build such bio-signatures by using targeted assays. In order to streamline such efforts, we developed a workflow to build dual binder sandwich immunoassays (SIA) and chose to evaluate this on proteins predicted to be secreted form cells and tissues. Utilizing the multiplexing capacities of the bead array technology, we first screened ~ 1,800 unique antibody pairs against 209 protein targets and collected data from dilution series of recombinant proteins as well as EDTA plasma. Employing 624 unique antibodies from the Human Protein Atlas, we obtained dilution-dependent curves in plasma and concentration-dependent curves of full-length proteins for 102 (49%) of the targets. For 22 protein assays, the longitudinal, inter-individual and technical performance...
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Authors: 16
Total Words: 14436
Unqiue Words: 3596

0.0 Mikeys
#8. A mechanism for ligand gated strand displacement in ZTP riboswitch transcription regulation
Eric J Strobel, Luyi Cheng, Katherine E Berman, Paul D Carlson, Julius B Lucks
Cotranscriptional RNA folding forms structural intermediates that can be critically important for RNA biogenesis. This is especially true for transcriptional riboswitches that must undergo ligand-dependent structural changes during transcription to regulate the synthesis of downstream genes. Here, we systematically map the folding states traversed by the Clostridium beijerinckii pfl riboswitch as it controls transcription termination in response to the purine biosynthetic intermediate ZMP. We find that after rearrangement of a non-native hairpin to form the ZTP aptamer, cotranscriptional ZMP binding stabilizes two structural elements that lead to antitermination by tuning the efficiency of terminator hairpin nucleation and strand displacement. We also uncover biases within natural ZTP riboswitch sequences that could avoid misfolded intermediates that disrupt function. Our findings establish a mechanism for ZTP riboswitch control of transcription that has similarities to the mechanisms of diverse riboswitches and provide evidence...
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2primeOH: Yesterday we posted a preprint for the latest @LucksLab RNA folding story. We uncovered how ZTP riboswitch structures control transcription termination and we think that one of these structures is under pressure to fold efficiently. https://t.co/6wuXwH68Xo
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0.0 Mikeys
#9. Fibril formation rewires interactome of the Alzheimer protein Tau by π-stacking
Luca Ferrari, Riccardo Stucci, Aikaterini Konstantoulea, Gerarda van de Kamp, Renate Kos, Willie J.C. Geerts, Friedrich G. Forster, Maarten Altelaar, Casper Hoogenraad, Stefan G.D. Rudiger
Aggregation of the Tau protein defines progression of neurodegenerative diseases, including Alzheimers Disease. Tau assembles into oligomers and fibrils. The molecular basis of their toxicity is poorly understood. Here we show that pi-stacking by Arginine side chains rewires the interactome of Tau upon aggregation. Oligomeric nano-aggregates scavenge the COPI complex, fibrils attract proteins involved in microtubule binding, RNA binding and phosphorylation. The aberrant interactors have disordered regions with unusual sequence features. Arginines are crucial to initiate such aberrant interactions. Remarkably, substitution of Arginines by Lysines abolishes scavenging, which indicates a key role for the pi-stacking of the Arginine side chain. The molecular chaperone Hsp90 tames such re-arrangements, which suggests that the natural protein quality control system can suppress aberrant interactions. Together, our data present a molecular mode of action for derailment of protein-protein interaction in neurodegeneration.
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biorxivpreprint: Fibril formation rewires interactome of the Alzheimer protein Tau by π-stacking https://t.co/bQdsnB5ADP #bioRxiv
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Authors: 10
Total Words: 12093
Unqiue Words: 3769

0.0 Mikeys
#10. High concentration and yield production of mannose from açaí (Euterpe oleracea) seeds via diluted-acid and mannanase-catalyzed hydrolysis
Alvaro Ferreira Monteiro, Ingrid Santos Miguez, João Pedro Rodrigues Barros Silva, Ayla Santana Silva
The açaí berry's seed corresponds to 85-95% of the fruit's weight and represents ~1.1 million tons of residue yearly accumulated in the Amazon region. This study confirmed that mannan is the major component of mature seeds, corresponding to 80% of the seed's total carbohydrates and about 50% of its dry weight. To convert this mannan content into mannose, a sequential process of diluted-acid and enzymatic hydrolysis was evaluated. Diluted-H2SO4 hydrolysis (3%-acid, 60-min, 121°C) resulted in a 30% mannan hydrolysis yield and 41.7 g/L of mannose. Because ~70% mannan remained in the seed, a mannanase-catalyzed hydrolysis was sequentially performed with 2-20% seed concentration, reaching 146.3 g/L of mannose and a 96.8% yield with 20% solids. As far as we know, this is the highest reported concentration of mannose produced from a residue. Thus, this work provides fundamental data for achieving high concentrations and yields of mannose from açaí seeds.
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biorxivpreprint: High concentration and yield production of mannose from acai (Euterpe oleracea) seeds via diluted-acid and mannanase-catalyzed hydrolysis https://t.co/gCmbcFdhxC #bioRxiv
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Authors: 4
Total Words: 10774
Unqiue Words: 3624

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