Top 10 Biorxiv Papers Today in Biochemistry


2.016 Mikeys
#1. Polycomb Cbx2 Condensates Assemble through Phase Separation
Roubina Tatavosian, Samantha Kent, Kyle Brown, Tingting Yao, Huy Nguyen Duc, Thao Ngoc Huynh, Chao Yu Zhen, Brian Ma, Haobin Wang, Xiaojun Ren
Polycomb group (PcG) proteins are master regulators of development and differentiation. Mutation and dysregulation of PcG genes cause developmental defects and cancer. PcG proteins form condensates in the nucleus of cells and these condensates are the physical sites of PcG-targeted gene silencing. However, the physiochemical principles underlying the PcG condensate formation remain unknown. Here we show that Polycomb repressive complex 1 (PRC1) protein Cbx2, one member of the Cbx family proteins, contains a long stretch of intrinsically disordered region (IDR). Cbx2 undergoes phase separation to form condensates. Cbx2 condensates exhibit liquid-like properties and can concentrate DNA and nucleosomes. We demonstrate that the conserved residues within the IDR promote the condensate formation in vitro and in vivo. We further indicate that H3K27me3 has minimal effects on the Cbx2 condensate formation while depletion of core PRC1 subunits facilitates the condensate formation. Thus, our results reveal that PcG condensates assemble...
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biorxivpreprint: Polycomb Cbx2 Condensates Assemble through Phase Separation https://t.co/USwkjoPTqU #bioRxiv
XR_Lab: Our first bioRxiv manuscript: Phase separation of Polycomb Cbx2 protein. Polycomb Cbx2 Condensates Assemble through Phase Separation https://t.co/tdwbvdVoBr
XR_Lab: Two labs reach the same conclusion. Polycomb Cbx2 Condensates Assemble through Phase Separation https://t.co/tdwbvdVoBr https://t.co/tdwbvdVoBr Phase separation and nucleosome compaction are governed by the same domain of Polycomb Repressive Complex 1 https://t.co/JCoazf2pzX
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Authors: 10
Total Words: 12596
Unqiue Words: 3958

2.011 Mikeys
#2. A Primase-Induced Conformational Switch Controls the Stability of the Bacterial Replisome
Enrico Monachino, Slobodan Jergic, Jacob S. Lewis, Zhi-Qiang Xu, Allen T.Y. Lo, Valerie L. O Shea, James M. Berger, Nicholas E. Dixon, Antoine M. van Oijen
Recent studies of bacterial DNA replication have led to a picture of the replisome as an entity that freely exchanges DNA polymerases and displays intermittent coupling between the helicase and polymerase(s). Challenging the textbook model of the polymerase holoenzyme acting as a stable complex coordinating the replisome, these observations suggest a role of the helicase as the central organizing hub. We show here that the molecular origin of this newly-found plasticity lies in the >400-fold increase in strength of the interaction between the polymerase holoenzyme and the replicative helicase upon association of the primase with the replisome. By combining in vitro ensemble-averaged and single-molecule assays, we demonstrate that this conformational switch operates during replication and promotes recruitment of multiple holoenzymes at the fork. Our observations provide a molecular mechanism for polymerase exchange and offer a revised model for the replication reaction that emphasizes its stochasticity.
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van__Oijen: After a decade of hard work by our talented team @uow @uowresearch @MolHorizons @ihmri, we've come a major step closer to understanding how bacteria copy their DNA. Executive summary: the brown bit tightens up the blue bits. Movie from @drewberryIV. https://t.co/5cl9mH0DlA https://t.co/QSStJjTHmd
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Sample Sizes : None.
Authors: 9
Total Words: 18398
Unqiue Words: 4348

0.0 Mikeys
#3. High accuracy protein structures from minimal sparse paramagnetic solid-state NMR restraints
Alberto Perez, Kari Gaalswyk, Christopher Jaroniec, Justin MacCallum
There is a pressing need for new computational tools to integrate data from diverse experimental approaches in structural biology. We present a strategy that combines sparse paramagnetic solid-state NMR restraints with physics-based atomistic simulations. Our approach explicitly accounts for uncertainty in the interpretation of experimental data through the use of a semi-quantitative mapping between the data and the restraint energy that is calibrated by extensive simulations. We apply our approach to solid-state NMR data for the model protein GB1 labeled with Cu2+-EDTA at six different sites. We are able to determine the structure to ca. 1 Å accuracy within a single day of computation on a modest GPU cluster. We further show that in 4 of 6 cases, the data from only a single paramagnetic tag are sufficient to fold the protein to high accuracy.
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jlmaccal: New preprint from my lab: High accuracy protein structures from minimal sparse solid-state NMR data. https://t.co/jBadDIUwUp
mrinal1989: High accuracy protein structures from minimal sparse paramagnetic solid-state NMR restraints https://t.co/84zGVxUVbE
jchodera: RT @jlmaccal: New preprint from my lab: High accuracy protein structures from minimal sparse solid-state NMR data. https://t.co/jBadDIUwUp
ElisaTelisa: RT @jlmaccal: New preprint from my lab: High accuracy protein structures from minimal sparse solid-state NMR data. https://t.co/jBadDIUwUp
letranger14: RT @jlmaccal: New preprint from my lab: High accuracy protein structures from minimal sparse solid-state NMR data. https://t.co/jBadDIUwUp
Al__Perez: RT @jlmaccal: New preprint from my lab: High accuracy protein structures from minimal sparse solid-state NMR data. https://t.co/jBadDIUwUp
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Authors: 4
Total Words: 5004
Unqiue Words: 1762

0.0 Mikeys
#4. Deconvolution of substrate processing by the 26S proteasome reveals a selective kinetic gateway to degradation
Jared AM Bard, Charlene Bashore, Ken C Dong, Andreas Martin
The 26S proteasome is the principle macromolecular machine responsible for protein degradation in eukaryotes. However, little is known about the detailed kinetics and coordination of the underlying substrate-processing steps of the proteasome, and their correlation with observed conformational states. Here, we used reconstituted 26S proteasomes with unnatural amino acid-attached fluorophores in a series of FRET and anisotropy-based assays to probe substrate-proteasome interactions, the individual steps of the processing pathway, and the conformational state of the proteasome itself. We develop a complete kinetic picture of proteasomal degradation, which reveals that the engagement steps prior to substrate commitment are fast relative to subsequent deubiquitination, translocation and unfolding. Furthermore, we find that non-ideal substrates are rapidly rejected by the proteasome, which thus employs a kinetic proofreading mechanism to ensure degradation fidelity and substrate prioritization.
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biorxivpreprint: Deconvolution of substrate processing by the 26S proteasome reveals a selective kinetic gateway to degradation https://t.co/1JCZWyxImZ #bioRxiv
AlanLHutchison: Excited to read @jabard89 new @biorxivpreprint "Deconvolution of substrate processing by the 26S proteasome reveals a selective kinetic gateway to degradation". Up and coming scientist soon joining the lab of @dallandrummond as a @bsdpostdoc! https://t.co/WTZG6y7hBu
proteazomnomnom: The preprint of our study on the kinetics of substrate processing by the 26S #proteasome is out: https://t.co/1wyK4wh5ym https://t.co/YJgs19b4xZ
WordenEvan: long time in the making. Complete deconvolution of substrate processing by the 26S proteasome. All kinetic steps revealed! Great work by my old lab @proteazomnomnom https://t.co/eMIGXfKdjK
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Authors: 4
Total Words: 14558
Unqiue Words: 3436

0.0 Mikeys
#5. Selective Permeability of Carboxysome Shell Pores to Anionic Molecules
Paween Mahinthichaichan, Dylan M Morris, Yi Wang, Grant J Jensen, Emad Tajkhorshid
Carboxysomes are closed polyhedral cellular microcompartments that increase the efficiency of carbon fixation in autotrophic bacteria. Carboxysome shells consist of small proteins that form hexameric units with semi-permeable central pores containing binding sites for anions. This feature is thought to selectively allow access to RuBisCO enzymes inside the carboxysome by HCO3- (the dominant form of CO2 in the aqueous solution at pH 7.4) but not O2, which leads to a non-productive reaction. To test this hypothesis, here we use molecular dynamics simulations to characterize the energetics and permeability of CO2, O2, and HCO3- through the central pores of two different shell proteins, namely, CsoS1A of α-carboxysome and CcmK4 of β-carboxysome shells. We find that the central pores are in fact selectively permeable to anions such as HCO3-, as predicted by the model.
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theJensenLab: Check out our new @biorxivpreprint with the Tajkhorshid group on the selective permeability of carboxysome shells: https://t.co/xx3pYiUPvV https://t.co/aPsXkMyIsV
CyanoLab: @joachimgoedhart https://t.co/eIpw0qm4as
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Authors: 5
Total Words: 6613
Unqiue Words: 2106

0.0 Mikeys
#6. A structure-based approach towards identification of inhibitory fragments for eleven-nineteen-leukemia protein (ENL) YEATS domain
David Heidenreich, Moses Moustakim, Jurema Schmidt, Daniel Merk, Paul E. Brennan, Oleg Fedorov, Apirat Chaikuad, Stefan Knapp
Lysine acetylation is an epigenetic mark that is principally recognized by bromodomains and recently structurally diverse YEATS domains also emerged as readers of lysine acetyl/acylations. Here we present a crystallography-based strategy and the discovery of fragments binding to the ENL YEATS domain, a potential drug target. Crystal structures combined with synthetic efforts led to the identification of a sub-micromolar binder, providing first starting points for the development of chemical probes for this reader domain family.
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Authors: 8
Total Words: 5519
Unqiue Words: 2036

0.0 Mikeys
#7. The Rhodobacter sphaeroides methionine sulfoxide reductase MsrP can reduce R- and S- diastereomers of methionine sulfoxide from a broad-spectrum of protein substrates.
Lionel Tarrago, Sandrine Grosse, Marina I Siponen, David Lemaire, Beatrice Alonso, Guylaine Miotello, Jean Armengaud, Pascal Arnoux, David Pignol, Monique Sabaty
Methionine (Met) is prone to oxidation and can be converted to Met sulfoxide (MetO), which exists as R- and S-diastereomers. MetO can be reduced back to Met by the ubiquitous methionine sulfoxide reductase (Msr) enzymes. Canonical MsrA and MsrB were shown as absolutely stereospecific for the reduction of S- and R-diastereomer, respectively. Recently, the molybdenum-containing protein MsrP, conserved in all gram-negative bacteria, was shown to be able to reduce MetO of periplasmic proteins without apparent stereospecificity in Escherichia coli. Here, we describe the substrate specificity of the Rhodobacter sphaeroides MsrP. Proteomics analysis coupled to enzymology approaches indicate that it reduces a broad spectrum of periplasmic oxidized proteins. Moreover, using model proteins, we demonstrated that RsMsrP preferentially reduces unfolded oxidized proteins and we confirmed that this enzyme, like its E. coli homolog, can reduce both R- and S-diastereomers of MetO with similar efficiency.
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Authors: 10
Total Words: 12882
Unqiue Words: 3919

0.0 Mikeys
#8. Requirements for efficient cotranscriptional regulatory switching in designed variants of the Bacillus subtilis pbuE adenine-responsive riboswitch
Lea K. Drogalis, Robert T. Batey
Riboswitches, generally located in the 5'-leader of bacterial mRNAs, direct expression via a small molecule-dependent structural switch informing the transcriptional or translational machinery. While the structure and function of riboswitch effector-binding (aptamer) domains have been intensely studied, only recently have the requirements for efficient linkage between small molecule binding and the structural switch in the cellular and cotranscriptional context begun to be actively explored. To address this, we have performed a structure-guided mutagenic analysis of the B. subtilis pbuE adenine-responsive riboswitch, one of the simplest riboswitches containing a secondary structural switch. Using a cell-based fluorescent protein reporter assay to assess ligand-dependent regulatory activity in E. coli, these studies revealed previously unrecognized features of the riboswitch. Most importantly, it was found that local and long-range conformational dynamics in two regions of the aptamer domain have a significant effect upon efficient...
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biorxivpreprint: Requirements for efficient cotranscriptional regulatory switching in designed variants of the Bacillus subtilis pbuE adenine-responsive riboswitch https://t.co/xbppKa1D9p #bioRxiv
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Authors: 2
Total Words: 11510
Unqiue Words: 2892

0.0 Mikeys
#9. IRES-mediated ribosome repositioning directs translation of a +1 overlapping ORF that enhances viral infection
Craig H Kerr, Qing S Wang, Kyung-Mee Moon, Kathleen Keatings, Douglas W Allan, Leonard J Foster, Eric Jan
RNA structures can interact with the ribosome to alter translational reading frame maintenance and promote recoding that result in alternative protein products. Here, we show that the internal ribosome entry site (IRES) from the dicistrovirus Cricket paralysis virus drives translation of the 0-frame viral polyprotein and an overlapping +1 open reading frame, called ORFx, via a novel mechanism whereby a subset of ribosomes recruited to the IRES bypasses downstream to resume translation at the +1-frame 13th non-AUG codon. A mutant of CrPV containing a stop codon in the +1 frame ORFx sequence, yet synonymous in the 0-frame, is attenuated compared to wild-type virus in a Drosophila infection model, indicating the importance of +1 ORFx expression in promoting viral pathogenesis. This work demonstrates a novel programmed IRES-mediated recoding strategy to increase viral coding capacity and impact virus infection, highlighting the diversity of RNA-driven translation initiation mechanisms in eukaryotes.
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Authors: 7
Total Words: 12227
Unqiue Words: 3559

0.0 Mikeys
#10. Identification of two principal amyloid-driving segments in variable domains of Ig light chains in AL amyloidosis
Boris Brumshtein, Shannon Esswein, Michael R Sawaya, Alan T Ly, Meytal Landau, David S Eisenberg
Systemic light chain amyloidosis (AL) is a disease caused by overexpression of monoclonal immunoglobulin light chains that form pathogenic amyloid fibrils. These amyloid fibrils deposit in tissues and cause organ failure. Proteins form amyloid fibrils when they partly or fully unfold and expose segments capable of stacking into β-sheets that pair forming a tight, dehydrated interface. These structures, termed steric zippers, constitute the spines of amyloid fibrils. Here, we identify segments within the variable domains of Ig light chains that drive the assembly of amyloid fibrils in AL. We demonstrate there are at least two such segments. Each one can drive amyloid fibril assembly independently of the other. Thus these two segments are therapeutic targets. In addition to elucidating the molecular pathogenesis of AL, these findings also provide an experimental approach to identify segments that drive fibril formation in other amyloid diseases.
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biorxivpreprint: Identification of two principal amyloid-driving segments in variable domains of Ig light chains in AL amyloidosis https://t.co/unD9fMsgbH #bioRxiv
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Authors: 6
Total Words: 8044
Unqiue Words: 2548

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