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Protein complex

Srijeeb Karmakar, Laipubam Gayatri Sharma, Abhishek Roy, Anjali Patel, Lalit Mohan Pandey
SNARE (Soluble NSF(N-ethylmaleimide-sensitive factor) Attachment Receptor) complex is a trimeric supramolecular organization of SNAP25, syntaxin, and VAMP which mediates fusion of synaptic vesicles with the presynaptic plasma membrane. The functioning of this entire protein assembly is dependent on its tetrahelical coiled coil structure alongside its interaction with a large spectrum of regulatory proteins like synaptotagmin, complexin, intersectin, etc. Defects arising in SNARE complex assembly due to mutations or faulty post-translational modifications are associated to severe synaptopathies like Schizophrenia and also proteopathies like Alzheimer's disease...
December 2, 2018: Neurochemistry International
Guillaume Bompard, Juliette van Dijk, Julien Cau, Yoann Lannay, Guillaume Marcellin, Aleksandra Lawera, Siem van der Laan, Krzysztof Rogowski
Tubulin glutamylation is a reversible posttranslational modification that accumulates on stable microtubules (MTs). While abnormally high levels of this modification lead to a number of disorders such as male sterility, retinal degeneration, and neurodegeneration, very little is known about the molecular mechanisms underlying the regulation of glutamylase activity. Here, we found that CSAP forms a complex with TTLL5, and we demonstrate that the two proteins regulate their reciprocal abundance. Moreover, we show that CSAP increases TTLL5-mediated glutamylation and identify the TTLL5-interacting domain...
December 4, 2018: Cell Reports
Anthony J Bainor, Siddharth Saini, Alexander Calderon, Raquel Casado-Polanco, Belén Giner-Ramirez, Claudia Moncada, David J Cantor, Amanda Ernlund, Larisa Litovchick, Gregory David
The mammalian DREAM complex is responsible for the transcriptional repression of hundreds of cell-cycle-related genes in quiescence. How the DREAM complex recruits chromatin-modifying entities to aid in its repression remains unknown. Using unbiased proteomics analysis, we have uncovered a robust association between the chromatin-associated Sin3B protein and the DREAM complex. We have determined that genetic inactivation of Sin3B results in the de-repression of DREAM target genes during quiescence but is insufficient to allow quiescent cells to resume proliferation...
December 4, 2018: Cell Reports
Julia Flis, Mikael Holm, Emily J Rundlet, Justus Loerke, Tarek Hilal, Marylena Dabrowski, Jörg Bürger, Thorsten Mielke, Scott C Blanchard, Christian M T Spahn, Tatyana V Budkevich
Translocation moves the tRNA2 ⋅mRNA module directionally through the ribosome during the elongation phase of protein synthesis. Although translocation is known to entail large conformational changes within both the ribosome and tRNA substrates, the orchestrated events that ensure the speed and fidelity of this critical aspect of the protein synthesis mechanism have not been fully elucidated. Here, we present three high-resolution structures of intermediates of translocation on the mammalian ribosome where, in contrast to bacteria, ribosomal complexes containing the translocase eEF2 and the complete tRNA2 ⋅mRNA module are trapped by the non-hydrolyzable GTP analog GMPPNP...
December 4, 2018: Cell Reports
Takaki Tokiwa, Shogo Nakano, Yuta Yamamoto, Takeshi Ishikawa, Sohei Ito, Vladimir Sladek, Kaori Fukuzawa, Yuji Mochizuki, Hiroaki Tokiwa, Fuminori Misaizu, Yasuteru Shigeta
In modern praxis, a knowledge-driven design of pharmaceutical compounds relies heavily on protein structure data. Nonetheless, quantification of the interaction between protein and ligand is of great importance in the theoretical evaluation of the ability of a pharmaceutical compound to comply with certain expectations. The FMO (fragment molecular orbital) method is handy in this regard. However, the physical complexity and the number of the interactions within a protein-ligand complex render analysis of the results somewhat complicated...
December 5, 2018: Journal of Chemical Information and Modeling
Neelanjan Mukherjee, Hans-Hermann Wessels, Svetlana Lebedeva, Marcin Sajek, Mahsa Ghanbari, Aitor Garzia, Alina Munteanu, Dilmurat Yusuf, Thalia Farazi, Jessica I Hoell, Kemal M Akat, Altuna Akalin, Thomas Tuschl, Uwe Ohler
RNA-binding proteins (RBPs) control and coordinate each stage in the life cycle of RNAs. Although in vivo binding sites of RBPs can now be determined genome-wide, most studies typically focused on individual RBPs. Here, we examined a large compendium of 114 high-quality transcriptome-wide in vivo RBP-RNA cross-linking interaction datasets generated by the same protocol in the same cell line and representing 64 distinct RBPs. Comparative analysis of categories of target RNA binding preference, sequence preference, and transcript region specificity was performed, and identified potential posttranscriptional regulatory modules, i...
December 5, 2018: Nucleic Acids Research
Florian Ehrlich, Heinz Fischer, Lutz Langbein, Silke Praetzel-Wunder, Bettina Ebner, Katarzyna Figlak, Anton Weissenbacher, Wolfgang Sipos, Erwin Tschachler, Leopold Eckhart
Keratins are the main intermediate filament proteins of epithelial cells. In keratinocytes of the mammalian epidermis they form a cytoskeleton that resists mechanical stress and thereby are essential for the function of the skin as a barrier against the environment. Here, we performed a comparative genomics study of epidermal keratin genes in terrestrial and fully aquatic mammals to determine adaptations of the epidermal keratin cytoskeleton to different environments. We show that keratins K5 and K14 of the innermost (basal), proliferation-competent layer of the epidermis are conserved in all mammals investigated...
December 4, 2018: Molecular Biology and Evolution
Sara K Young-Baird, Byung-Sik Shin, Thomas E Dever
The heterotrimeric eukaryotic translation initiation factor (eIF) 2 plays critical roles in delivering initiator Met-tRNAiMet to the 40S ribosomal subunit and in selecting the translation initiation site. Genetic analyses of patients with MEHMO syndrome, an X-linked intellectual disability syndrome, have identified several unique mutations in the EIF2S3 gene that encodes the γ subunit of eIF2. To gain insights into the molecular consequences of MEHMO syndrome mutations on eIF2 function, we generated a yeast model of the human eIF2γ-I259M mutant, previously identified in a patient with MEHMO syndrome...
December 4, 2018: Nucleic Acids Research
Hassan Zafar, Milton H Saier
The communities of beneficial bacteria that live in our intestines, the gut microbiome, are important for the development and function of the immune system. Bacteroides species make up a significant fraction of the human gut microbiome, and can be probiotic and pathogenic, depending upon various genetic and environmental factors. These can cause disease conditions such as intra-abdominal sepsis, appendicitis, bacteremia, endocarditis, pericarditis, skin infections, brain abscesses and meningitis. In this study, we identify the transport systems and predict their substrates within seven Bacteroides species, all shown to be probiotic; however, four of them (B...
2018: PloS One
Davis C Woodworth, Adelle Dagher, Adam Curatolo, Monisha Sachdev, Cody Ashe-McNalley, Bruce D Naliboff, Jennifer S Labus, J Richard Landis, Jason J Kutch, Emeran A Mayer, Richard S Lee, Marsha A Moses, Benjamin M Ellingson
The Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network has yielded neuroimaging and urinary biomarker findings that highlight unique alterations in brain structure and in urinary proteins related to tissue remodeling and vascular structure in patients with Urological Chronic Pelvic Pain Syndrome (UCPPS). We hypothesized that localized changes in diffusion tensor imaging (DTI) measurements might be associated with corresponding changes in urinary protein levels in UCPPS. To test this hypothesis, we created statistical parameter maps depicting the linear correlation between DTI measurements (fractional anisotropy (FA) and apparent diffusion coefficient (ADC)) and urinary protein quantification (MMP2, MMP9, NGAL, MMP9/NGAL complex, and VEGF) in 30 UCPPS patients from the MAPP Research Network, after accounting for clinical covariates...
2018: PloS One
Erich Michel, Oliver Zerbe, Andreas Plückthun
Designed armadillo repeat proteins (dArmRPs) are modular peptide binders composed of N- and C-terminal capping repeats Y and A and a variable number of internal modules M that each specifically recognize two amino acids of the target peptide. Complementary fragments of dArmRPs obtained by splitting the protein between helices H1 and H2 of an internal module show conditional and specific assembly only in presence of a target peptide (Michel et al., 2018). Here, we investigate dArmRP fragments that already spontaneously assemble with high affinity, e...
December 1, 2018: Biological Chemistry
Arne Skerra, Mikhail Barkovskiy, Elena Ilyukhina, Martin Dauner, Andreas Eichinger
Colchicine is a toxic alkaloid prevalent in autumn crocus (Colchicum autumnale) that binds to tubulin and inhibits polymerization of microtubules. Using combinatorial and rational protein design, we have developed an artificial binding protein based on the human lipocalin 2 that binds colchicine with a dissociation constant of 120 pM, i.e. 10 000-fold stronger than tubulin. Crystallographic analysis of the engineered lipocalin, dubbed Colchicalin, revealed major structural changes in the flexible loop region that forms the ligand pocket at one end of the eight-stranded β-barrel, resulting in a lid-like structure over the deeply buried colchicine...
December 1, 2018: Biological Chemistry
Claudia Schmidt, Lucia Albrecht, Shantheya Balasupramaniam, Rainer Misgeld, Bianka Karge, Mark Brönstrup, Aram Prokop, Knut Baumann, Stephan Reichl, Ingo Ott
Gold complexes with N-heterocyclic carbene (NHC) ligands have been attracting major attention in medicinal inorganic chemistry based on their favorable antiproliferative effects and the structural versatility of the coordinated NHC ligands. Here we present a novel complex of the type (NHC)2Au+, which represents a substantially improved and selective TrxR inhibitor compared to close structural analogues. The complex is highly stable in various solutions over 96 hours, however, comparative cellular uptake studies indicate metabolic transformations inside cells over time...
December 5, 2018: Metallomics: Integrated Biometal Science
Deliang Chen, Yibao Li, Wei Guo, Yongdong Li, Tor Savidge, Xun Li, Xiaolin Fan
Metal ions are important regulatory cofactors in a wide variety of proteins. Conventional wisdom suggests that stronger metal-ligand interactions have a larger effect on the ligand binding affinity. However, some experimental data do not support this conventional wisdom. In this study, we used a theoretical derivation approach to explore the effect of metal-ligand interactions on ligand binding affinities. Both theoretical derivation and experimental data indicate that metal-ligand interactions weaken the original interactions of the metal ions, which reduce the contributions of the metal-ligand interactions to the ligand binding affinities...
December 5, 2018: Physical Chemistry Chemical Physics: PCCP
Fabrício G Gonçalves, Tomás de Andrade L Freddi, Ajay Taranath, Rahul Lakshmanan, Robert Goetti, Fabricio S Feltrin, Kshitij Mankad, Sara R Teixeira, Prasad B Hanagandi, Filippo Arrigoni
Mutations causing dysfunction of the tubulins and microtubule-associated proteins, otherwise known as tubulinopathies, are a group of recently described entities, that lead to complex brain malformations. An understanding of the fundamental principles of operation of the cytoskeleton and compounds in particular microtubules, actin, and microtubule-associated proteins, can assist in the interpretation of the imaging findings of tubulinopathies. Somewhat consistent morphological imaging patterns have been described in tubulinopathies such as dysmorphic basal ganglia-the hallmark (found in 75% of cases), callosal dysgenesis, cerebellar hypoplasia/dysplasia, and cortical malformations, most notably lissencephaly...
December 2018: Topics in Magnetic Resonance Imaging: TMRI
Yu-Chen Chen, Pei-Heng Jiang, Hsuan-Ming Chen, Chang-Han Chen, Yi-Ting Wang, Yu-Ju Chen, Chia-Jung Yu, Shu-Chun Teng
Aging is an intricate phenomenon associated with the gradual loss of physiological functions, and both nutrient sensing and proteostasis control lifespan. Although multiple approaches have facilitated the identification of candidate genes that govern longevity, the molecular mechanisms that link aging pathways are still elusive. Here, we conducted a quantitative mass spectrometry screen and identified all phosphorylation/dephosphorylation sites on yeast proteins that significantly responded to calorie restriction, a well-established approach to extend lifespan...
December 5, 2018: ELife
Yang Zhang, Jingyi Zou, Xiaomin Zhao, Zhenghong Yuan, Zhigang Yi
Daclatasvir (DCV) is a highly potent direct-acting antiviral that targets the non-structural protein 5A (NS5A) of hepatitis C virus (HCV) and has been used with great clinical success. Previous studies have demonstrated its impact on viral replication complex assembly. However, the precise mechanisms by which DCV impairs the replication complex assembly remains elusive. In this study, by using HCV subgenomic replicons and a viral replicase assembly surrogate system in which the HCV NS3-5B polyprotein is expressed to mimic the viral replicase assembly, we assessed the impact of DCV on the aggregation and tertiary structure of NS5A, the protein-protein interactions within the viral replicase and the quaternary structure of the viral replicase...
December 5, 2018: Journal of General Virology
Sarmistha Majumdar, Debadrita Basu, Shubhra Ghosh Dastidar
The α,β-tubulin is the building block of the microtubules, which gets associated with and dissociated from the microtubular architecture complying with the dynamic instability of the microtubules. This dynamics has direct relation with the spindle formation by the microtubules and cell division kinetics. E7010 is one of the promising ligands of α,β-tubulin protein that binds at the core of this protein and can diminish the protein's ability to fit to a growing microtubule; thus frustrates the cell division...
December 5, 2018: Journal of Chemical Information and Modeling
Yilan Ouyang, Xiaorui Han, Qiangwei Xia, Jianle Chen, Sheila Velagapudi, Ke Xia, Zhenqing Zhang, Robert J Linhardt
Glycosaminoglycans (GAGs) are biologically and pharmacologically important linear, anionic polysaccharides containing various repeating disaccharides sequences. The analysis of these polysaccharides generally relies on their chemical or enzymatic breakdown to disaccharide units that are separated, by chromatography or electrophoresis, and detected, by UV, fluorescence or mass spectrometry (MS). Isoelectric focusing (IEF) is an important analytical technique with high resolving power for the separation of analytes exhibiting differences in isoelectric points...
December 5, 2018: Analytical Chemistry
Vladyslava Kovalska, Marina Kuperman, Mykhaylo Losytskyy, Serhii Vakarov, Slawomir Potocki, Sergiy Yarmoluk, Yan Voloshin, Oleg Varzatskii, Elzbieta Gumienna-Kontecka
An ability of inherently achiral macrobicyclic metal complexes iron(ii) clathrochelates to acquire an induced CD (ICD) output in the visible spectral range upon interaction with bovine serum albumin (BSA) was recently discovered. In the present work, the CD-reporting properties of iron(ii) clathrochelates to proteins and the thermodynamic parameters of their binding to albumins are evaluated. It is shown that iron(ii) clathrochelates functionalized by six ribbed carboxyphenylsulfide groups are able to discriminate between serum albumins of relative structure (here human and bovine albumins) by giving distinct ICD spectra...
December 5, 2018: Metallomics: Integrated Biometal Science
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