Top 8 Biorxiv Papers Today in Biochemistry


2.029 Mikeys
#1. α-carboxysome formation is mediated by the multivalent and disordered protein CsoS2
Luke M Oltrogge, Thawatchai Chaijarasphong, Allen W Chen, Eric R Bolin, Susan Marqusee, David F Savage
Carboxysomes are bacterial microcompartments that function as the centerpiece of the bacterial CO2-concentrating mechanism, feeding high concentrations of CO2 to the enzyme Rubisco for fixation. The carboxysome self-assembles from thousands of individual proteins into icosahedral-like particles with a dense enzyme cargo encapsulated within a proteinaceous shell. In the case of the α-carboxysome, there is little molecular insight into protein-protein interactions which drive the assembly process. Here we show that the N-terminus of CsoS2, an intrinsically disordered protein found in the α-carboxysome, possesses a repeated peptide sequence that binds Rubisco. X-ray structural analysis of the peptide bound to Rubisco reveals a series of conserved electrostatic interactions that are only made with properly assembled hexadecameric Rubisco. Although biophysical measurements indicate this single interaction is weak, its implicit multivalency induces high-affinity binding through avidity. Taken together, our results indicate CsoS2 acts as...
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biorxivpreprint: α-carboxysome formation is mediated by the multivalent and disordered protein CsoS2 https://t.co/vTsxqehzPo #bioRxiv
3rdFloorTom: @SavageCatsOnly https://t.co/FlCP1Kf79z Wooooo!
CyanoLab: RT @biorxivpreprint: α-carboxysome formation is mediated by the multivalent and disordered protein CsoS2 https://t.co/vTsxqehzPo #bioRxiv
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Authors: 6
Total Words: 0
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2.014 Mikeys
#2. Cryo-EM structure of the Hedgehog release protein Dispatched
Fabien Cannac, Chao Qi, Julia Falschlunger, George Hausmann, Konrad Basler, Volodymyr M. Korkhov
The Hedgehog signaling pathway controls embryonic development and adult tissue homeostasis in multicellular organisms. In Drosophila melanogaster, the pathway is primed by secretion of a dually lipid-modified morphogen, Hedgehog (Hh), a process dependent on a membrane-integral protein Dispatched. Although Dispatched is a critical component of the pathway, the structural basis of its activity has so far not been described. Here, we describe a cryo-EM structure of the Drosophila melanogaster Dispatched at 3.2 Å resolution. The ectodomains of Dispatched adopt an open conformation suggestive of a receptor-chaperone role. A 3D reconstruction of Dispatched bound to Hh confirms the ability of Dispatched to bind Hh but using a unique mode distinct from those previously observed in structures of Hh complexes. The structure may represent the state of the complex that precedes shedding of Hh from the surface of the morphogen-releasing cell.
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biorxivpreprint: Cryo-EM structure of the Hedgehog release protein Dispatched https://t.co/Gwp3foYpsz #bioRxiv
cryoEM_Papers: Cryo-EM structure of the Hedgehog release protein Dispatched https://t.co/0WL9nnfMST
t2438: RT @cryoEM_Papers: Cryo-EM structure of the Hedgehog release protein Dispatched https://t.co/0WL9nnfMST
MartaUkleja: RT @cryoEM_Papers: Cryo-EM structure of the Hedgehog release protein Dispatched https://t.co/0WL9nnfMST
Lue_Wei: RT @biorxivpreprint: Cryo-EM structure of the Hedgehog release protein Dispatched https://t.co/Gwp3foYpsz #bioRxiv
3v3v2: RT @biorxivpreprint: Cryo-EM structure of the Hedgehog release protein Dispatched https://t.co/Gwp3foYpsz #bioRxiv
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2.009 Mikeys
#3. Dysregulation of HSP27 oligomerization and interactions by a neuropathy-causing mutation in the C-terminal IPV motif
T. Reid Alderson, Elias Adriaenssens, Bob Asselbergh, Iva Pritisanac, Heidi Y. Gastall, Marielle Walti, John M. Louis, Vincent Timmerman, Andrew Baldwin, Justin L. P. Benesch
HSP27 (HSPB1) is a systemically expressed human small heat-shock protein that forms large, dynamic oligomers and functions in various aspects of cellular homeostasis. Mutations in HSP27 cause Charcot-Marie-Tooth disease, the most commonly inherited disorder of the peripheral nervous system. A particularly severe form of the disease is triggered by the P182L mutation within the conserved C-terminal IPV motif of HSP27, also known as the IxI/V motif. Here, we observed that the P182L variant of HSP27 lost its ability to prevent the aggregation of client proteins and formed significantly larger oligomers both in vitro and in vivo . NMR spectroscopy revealed that P182L binds its α-crystallin domain with a significantly lower affinity and association rate, thus rendering the binding site more available for other interactors. We identified 22 IxI/V-containing proteins that are known to interact with HSP27 and could therefore bind with enhanced affinity to the P182L variant. Co-immunoprecipitation experiments indicate that the co-chaperone...
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biorxivpreprint: Dysregulation of HSP27 oligomerization and interactions by a neuropathy-causing mutation in the C-terminal IPV motif https://t.co/5rEytlOqNe #bioRxiv
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Authors: 10
Total Words: 19366
Unqiue Words: 5462

2.008 Mikeys
#4. The biosynthetic gene cluster of the C-nucleoside antibiotic pyrazomycin with a rare pyrazole moiety
Guiyun Zhao, Shunyu Yao, Kristina W Rothchild, Tengfei Liu, Yu Liu, Jiazhang Lian, Hai-Yan He, Katherine S Ryan, Yi-Ling Du
Pyrazomycin is a rare C-nucleoside antibiotic with a naturally occurring pyrazole ring, whose biosynthetic origin has remained obscure for decades. In this study, we report the identification of the gene cluster responsible for pyrazomycin biosynthesis in Streptomyces candidus NRRL 3601, revealing that StrR-family regulator PyrR is the cluster-situated transcriptional activator governing pyrazomycin biosynthesis. Furthermore, our results from in vivo reconstitution and stable-isotope feeding experiments support that PyrN is a new nitrogen-nitrogen bond forming enzyme linking the ε-NH2 nitrogen of L-N6-OH-lysine and α-NH2 nitrogen of L-glutamate. This study lays the foundation for further genetic and biochemical characterization of pyrazomycin pathway enzymes constructing the characteristic pyrazole ring.
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_abew_: Another route to the biosynthesis of N–N containing natural products! https://t.co/pXoNYjUJnj
wmwuest: RT @_abew_: Another route to the biosynthesis of N–N containing natural products! https://t.co/pXoNYjUJnj
MathaCMU: RT @_abew_: Another route to the biosynthesis of N–N containing natural products! https://t.co/pXoNYjUJnj
pnleao: RT @_abew_: Another route to the biosynthesis of N–N containing natural products! https://t.co/pXoNYjUJnj
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Authors: 9
Total Words: 4051
Unqiue Words: 1553

2.007 Mikeys
#5. Molecular basis for allosteric regulation of the type 2 ryanodine receptor channel gating by key modulators
Ximin Chi, Deshun Gong, Kang Ren, Gewei Zhou, Gaoxingyu Huang, Jianlin Lei, Qiang Zhou, Nieng Yan
The type-2 ryanodine receptor (RyR2) is responsible for releasing Ca2+ from the sarcoplasmic reticulum of cardiomyocytes, subsequently leading to muscle contraction. Here, we report four cryo-EM structures of porcine RyR2 bound to distinct modulators that collectively provide mechanistic insight into RyR2 regulation. Ca2+ alone induces a contraction of the Central domain that facilitates the dilation of S6 bundle, but is insufficient to open the pore. The small molecule agonist PCB95 helps Ca2+ to overcome the barrier for opening. FKBP12.6 induces a relaxation of the Central domain that decouples it from the S6 bundle, stabilizing RyR2 in a closed state. Caffeine locks the Central domain in a constitutively contracted state, while further addition of ATP opens the channel by strengthening the coupling between the U-motif and S6. Our study marks an important step towards mechanistic understanding of the complicated regulation of this key channel whose aberrant activity engenders life-threatening cardiac disorders.
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biorxivpreprint: Molecular basis for allosteric regulation of the type 2 ryanodine receptor channel gating by key modulators https://t.co/UA5jHNG1Cn #bioRxiv
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Authors: 8
Total Words: 9028
Unqiue Words: 2415

1.998 Mikeys
#6. A selective and rapid cell-permeable inhibitor of human caspase-3
Angelo Solania, Gonzalo Gonzalez-Paez, Dennis Wolan
The individual roles and overlapping functionalities the twelve human caspases have during apoptosis and other cellular processes remain poorly resolved primarily due to a lack of chemical tools. Here we present a new selective caspase-3 inhibitor, termed Ac-ATS010-KE, with rapid and irreversible binding kinetics. Relative to previously designed caspase-3-selective molecules that have tremendously abated inhibitory rates and thus limited use in biological settings, the improved kinetics of Ac-ATS010-KE permit its use in a cell-based capacity. We demonstrate that Ac-ATS010-KE prevents apoptosis with comparable efficacy to the general caspase inhibitor Ac-DEVD-KE and surprisingly does so without side-chain methylation. This observation is in contrast to the well-established peptide modification strategy typically employed for improving cellular permeability. Ac-ATS010-KE protects against extrinsic apoptosis, which demonstrates the utility of a thiophene carboxylate leaving group in biological settings, challenges the requisite...
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HyserLab: RT @biorxivpreprint: A selective and rapid cell-permeable inhibitor of human caspase-3 https://t.co/83egEPJfwG #bioRxiv
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Authors: 3
Total Words: 6667
Unqiue Words: 2375

1.997 Mikeys
#7. Towards the application of Tc toxins as a universal protein translocation system
Daniel Roderer, Evelyn Schubert, Oleg Sitsel, Stefan Raunser
Tc toxins are large bacterial protein complexes that inject cytotoxic enzymes into target cells using a sophisticated syringe-like mechanism. Tc toxins are composed of a membrane translocator and a cocoon that encapsulates a toxic enzyme. The toxic enzyme varies between Tc toxins from different species and is not conserved. Here, we investigated whether the toxic enzyme can be replaced by other small proteins of different origin and properties, namely human Cdc42, herpes simplex virus ICP47, Arabidopsis thaliana iLOV, Escherichia coli DHFR, human Ras-binding domain of CRAF kinase, and tobacco etch virus protease. Using a combination of electron microscopy, X-ray crystallography and in vitro translocation assays, we demonstrate that it is possible to turn Tc toxins into customizable molecular syringes for delivering proteins of interest across membranes. We also infer the guidelines that protein cargos must obey in terms of size, charge, and fold in order to successfully take advantage of this new universal protein translocation system.
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thparietallobe: RT @biorxivpreprint: Towards the application of Tc toxins as a universal protein translocation system https://t.co/rNZppoeQBS #bioRxiv
pickettbd: RT @biorxivpreprint: Towards the application of Tc toxins as a universal protein translocation system https://t.co/rNZppoeQBS #bioRxiv
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Authors: 4
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1.996 Mikeys
#8. A novel mass assay to measure phosphatidylinositol-5-phosphate from cells and tissues
Avishek Ghosh, Sanjeev Sharma, Dhananjay Shinde, Visvanathan Ramya, Padinjat Raghu
Phosphatidylinositol-5-phosphate (PI5P) is a low abundance lipid proposed to have functions in cell migration, DNA damage responses, receptor trafficking and insulin signalling in metazoans. However, studies of PI5P function are limited by the lack of scalable techniques to quantify its level from cells and tissues in multicellular organisms. Currently, PI5P measurement requires the use of radionuclide labelling approaches that are not easily applicable in tissues or in vivo samples. In this study, we describe a simple and reliable, non-radioactive mass assay to measure total PI5P levels from cells and tissues of Drosophila , a genetically tractable multicellular model. We use 18O-ATP to label PI5P from tissue extracts while converting it into PI(4,5)P2 using an in vitro kinase reaction. The product of this reaction can be selectively detected and quantified with high sensitivity using a liquid chromatography-tandem mass spectrometry platform. Further, using this method, we capture and quantify the unique acyl chain composition of...
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Authors: 5
Total Words: 2183
Unqiue Words: 887

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