Top 5 Biorxiv Papers Today in Biochemistry


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#1. Crystal structure and interaction studies of human DHTKD1 provide insight into a mitochondrial megacomplex in lysine catabolism
Gustavo A. Bezerra, William R. Foster, Henry J. Bailey, Kevin G. Hicks, Sven W. Sauer, Bianca Dimitrov, Juergen G. Okun, Jared Rutter, Stefan Koelker, Wyatt W. Yue
DHTKD1 is a lesser-studied E1 enzyme belonging to the family of 2-oxoacid dehydrogenases. DHTKD1, in complex with the E2 (dihydrolipoamide succinyltransferase, DLST) and E3 (lipoamide dehydrogenase, DLD) components, is implicated in lysine and tryptophan catabolism by catalysing the oxidative decarboxylation of 2-oxoadipate (2OA) in the mitochondria. Here, we solved the crystal structure of human DHTKD1 at 1.9 Å resolution in binary complex with the thiamine diphosphate (ThDP) cofactor. Our structure explains the evolutionary divergence of DHTKD1 from the well-characterized homologue 2-oxoglutarate (2OG) dehydrogenase, in its preference for the larger 2OA substrate than 2OG. Inherited DHTKD1 missense mutations cause the lysine metabolic condition 2-aminoadipic and 2-oxoadipic aciduria. Reconstruction of the missense variant proteins reveal their underlying molecular defects, which include protein destabilisation, disruption of protein-protein interactions, and alterations in the protein surface. We further generated a 5.0 Å...
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biorxivpreprint: Crystal structure and interaction studies of human DHTKD1 provide insight into a mitochondrial megacomplex in lysine catabolism https://t.co/fD9bT5MpEk #bioRxiv
YueLabSGC: Thrilled to have submitted our manuscript on DHTKD1 structure & interaction to @biorxivpreprint, back-to-back with impressive manuscript from @SanderHouten @LazarusLab on DHTKD1 structure & inhibition. Way to go, lysine metabolism! https://t.co/nEd4dKwEmC https://t.co/5k8P9fy7az https://t.co/s3bETcHDu8
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Authors: 10
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#2. Specialisation of ribosomes in gonads through paralog-switching
Julie L Aspden, Juan Fontana, Mary J O'Connell, Charley GP McCarthy, Karl Norris, Michaela Agapiou, Tayah Stephanie Hopes
Ribosomes have long been thought of as homogeneous, macromolecular machines but recent evidence suggests they are heterogeneous and their specialisation can regulate translation. Here, we have characterised ribosomal protein heterogeneity across 5 tissues of Drosophila melanogaster. We find that testis and ovary contain the most heterogeneous ribosome populations, and that specialisation in these tissues occurs through paralog-switching. For the first time, we have solved structures of ribosomes purified from in vivo tissues by cryo-EM, revealing differences in precise ribosomal arrangement for testis and ovary 80S ribosomes. Differences in the amino acid composition of paralog pairs and their localisation on the ribosome exterior indicate paralog-switching could alter the ribosome surface, enabling different proteins to regulate translation. One testis-specific paralog-switching pair is also found in humans, suggesting this is a conserved site of ribosome specialisation. Overall, this work allows us to propose possible mechanisms...
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cryoEM_Papers: Specialisation of ribosomes in gonads through paralog-switching https://t.co/UFKOlkPWds
ClementYChow: RT @biorxivpreprint: Specialisation of ribosomes in gonads through paralog-switching https://t.co/Nc77dds9A1 #bioRxiv
adernburg: RT @biorxivpreprint: Specialisation of ribosomes in gonads through paralog-switching https://t.co/Nc77dds9A1 #bioRxiv
JamesPBLloyd: RT @biorxivpreprint: Specialisation of ribosomes in gonads through paralog-switching https://t.co/Nc77dds9A1 #bioRxiv
juliusbrennecke: RT @biorxivpreprint: Specialisation of ribosomes in gonads through paralog-switching https://t.co/Nc77dds9A1 #bioRxiv
jhdcate: RT @biorxivpreprint: Specialisation of ribosomes in gonads through paralog-switching https://t.co/Nc77dds9A1 #bioRxiv
JunhyongKim: RT @biorxivpreprint: Specialisation of ribosomes in gonads through paralog-switching https://t.co/Nc77dds9A1 #bioRxiv
Lord_of_Flyz: RT @biorxivpreprint: Specialisation of ribosomes in gonads through paralog-switching https://t.co/Nc77dds9A1 #bioRxiv
zeqiraj: RT @biorxivpreprint: Specialisation of ribosomes in gonads through paralog-switching https://t.co/Nc77dds9A1 #bioRxiv
HawleLab: RT @biorxivpreprint: Specialisation of ribosomes in gonads through paralog-switching https://t.co/Nc77dds9A1 #bioRxiv
flugel5555: RT @cryoEM_Papers: Specialisation of ribosomes in gonads through paralog-switching https://t.co/UFKOlkPWds
DrMattByrne: RT @biorxivpreprint: Specialisation of ribosomes in gonads through paralog-switching https://t.co/Nc77dds9A1 #bioRxiv
SimonLCurrie: RT @biorxivpreprint: Specialisation of ribosomes in gonads through paralog-switching https://t.co/Nc77dds9A1 #bioRxiv
RaviTharakan: RT @biorxivpreprint: Specialisation of ribosomes in gonads through paralog-switching https://t.co/Nc77dds9A1 #bioRxiv
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#3. Development of high-throughput screening assays for profiling snake venom Phospholipase A2 activity after high resolution chromatographic fractionation
Kristina BM Still, Julien R Slagboom, Sarah Kidwai, Chunfang Xie, Bastiaan Eisses, Freek J Vonk, Govert W Somsen, Nicholas R Casewell, Jeroen Kool
Many organisms, ranging from plants to mammals, contain phospholipase A2 enzymes (PLA2s), which catalyze the production of lysophospholipids and fatty acid proinflammatory mediators. PLA2s are also common constituents of animal venoms, including bees, scorpions and snakes, and they cause a wide variety of toxic effects including neuro-, myo-, cyto-, and cardio-toxicity, anticoagulation and edema. The aim of this study was to develop a generic method for profiling enzymatically active PLA2s in snake venoms after chromatographic separation. For this, low-volume high-throughput assays for assessment of enzymatic PLA2 activity were evaluated and optimized. Subsequently, the assays were incorporated into a nanofractionation platform that combines high resolution fractionation of crude venoms by liquid chromatography (LC) with bioassaying in 384-well plate format, and parallel mass spectrometric (MS) detection for toxin identification. The miniaturized assays developed are based on absorbance or fluorescence detection (respectively,...
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Authors: 9
Total Words: 9609
Unqiue Words: 2567

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#4. Production and Purification of Endogenously Modified tRNA-Derived Small RNAs
Aleksej Drino, Vera Oberbauer, Conor Troger, Eva Janisiw, Dorothea Anrather, Markus Hartl, Steffen Kaiser, Stefanie Kellner, Matthias R. Schaefer
During particular stress conditions, transfer RNAs (tRNAs) become substrates of stress-induced endonucleases, resulting in the production of distinct tRNA-derived small RNAs (tsRNAs). These small RNAs have been implicated in a wide range of biological processes, but how isoacceptor and even isodecoder-specific tsRNAs act at the molecular level is still poorly understood. Importantly, stress-induced tRNA cleavage affects only a few tRNAs of a given isoacceptor or isodecoder, raising the question as to how such limited molecule numbers could exert measurable biological impact. While the molecular function of individual tsRNAs is likely mediated through association with other molecules, addressing the interactome of specific tsRNAs has only been attempted by using synthetic RNA sequences. Since tRNAs carry post-transcriptional modifications, tsRNAs are likely modified but the extent of their modifications remains largely unknown. Here, we developed a biochemical framework for the production and purification of specific tsRNAs using...
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biorxivpreprint: Production and Purification of Endogenously Modified tRNA-Derived Small RNAs https://t.co/OQLSoKYvkP #bioRxiv
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#5. Inhibition and Crystal Structure of the Human DHTKD1-Thiamin Diphosphate Complex
João Leandro, Susmita Khamrui, Hui Wang, Chalada Suebsuwong, Natalia S Nemeria, Khoi Huynh, Moses Moustakim, Cody Secor, May Wang, Tetyana Dodatko, Brandon Stauffer, Christopher G Wilson, Chunli Yu, Michelle R Arkin, Frank Jordan, Roberto Sanchez, Robert J DeVita, Michael B Lazarus, Sander M Houten
DHTKD1 is the E1 component of the 2-oxoadipic acid dehydrogenase complex (OADHc), which functions in the L-lysine degradation pathway. Mutations in DHTKD1 have been associated with 2-aminoadipic and 2-oxoadipic aciduria, Charcot-Marie-Tooth disease type 2Q (CMT2Q) and eosinophilic esophagitis (EoE). A crystal structure and inhibitors of DHTKD1 could improve the understanding of these clinically distinct disorders, but are currently not available. Here we report the identification of adipoylphosphonic acid and tenatoprazole as DHTKD1 inhibitors using targeted and high throughput screening, respectively. We furthermore elucidate the DHTKD1 crystal structure with thiamin diphosphate bound at 2.1 Å. The protein assembles as a dimer with residues from both monomers contributing to cofactor binding. We also report the impact of ten DHTKD1 missense mutations on the encoded proteins by enzyme kinetics, thermal stability and structural modeling. Some DHTKD1 variants displayed impaired folding (S777P and S862I), whereas other substitutions...
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SanderHouten: RT @biorxivpreprint: Inhibition and Crystal Structure of the Human DHTKD1-Thiamin Diphosphate Complex https://t.co/hyrLzZkbT8 #bioRxiv
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Authors: 19
Total Words: 10435
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