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Unstructured Proteins

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https://www.readbyqxmd.com/read/28821615/distinct-structural-mechanisms-determine-substrate-affinity-and-kinase-activity-of-protein-kinase-c%C3%AE
#1
Sangbae Lee, Titu Devamani, Hyun Deok Song, Manbir Sandhu, Adrien Larsen, Ruth Sommese, Abhinandan Jain, Nagarajan Vaidehi, Sivaraj Sivaramakrishnan
Protein kinase Cα (PKCα) belongs to the family of AGC kinases that phosphorylate multiple peptide substrates. While the consensus sequence motif has been identified and used to explain substrate specificity for PKCα, it does not inform the structural basis of substrate binding and kinase activity for diverse substrates phosphorylated by this kinase. The transient, dynamic, and unstructured nature of this protein-protein interaction has limited structural mapping of kinase-substrate interfaces. Here, using multiscale MD simulation-based predictions and FRET sensor-based experiments, we investigated the conformational dynamics of the kinase-substrate interface...
August 15, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28808112/regulation-of-perforin-activation-and-pre-synaptic-toxicity-through-c-terminal-glycosylation
#2
Imran G House, Colin M House, Amelia J Brennan, Omer Gilan, Mark A Dawson, James C Whisstock, Ruby Hp Law, Joseph A Trapani, Ilia Voskoboinik
Perforin is a highly cytotoxic pore-forming protein essential for immune surveillance by cytotoxic lymphocytes. Prior to delivery to target cells by exocytosis, perforin is stored in acidic secretory granules where it remains functionally inert. However, how cytotoxic lymphocytes remain protected from their own perforin prior to its export to secretory granules, particularly in the Ca(2+)-rich endoplasmic reticulum, remains unknown. Here, we show that N-linked glycosylation of the perforin C-terminus at Asn549 within the endoplasmic reticulum inhibits oligomerisation of perforin monomers and thus protects the host cell from premature pore formation...
August 14, 2017: EMBO Reports
https://www.readbyqxmd.com/read/28807826/structural-plasticity-of-t4-transcription-co-activator-gp33-revealed-by-a-protease-resistant-unfolded-state
#3
Radhakrishnan Mahalakshmi, Svetlana Rajkumar Maurya, Bhawna Burdak, Parini Surti, Manoj S Patel, Vikas Jain
Gene 33 protein (gp33) is a transcriptional coactivator for late genes of the T4 bacteriophage. gp33 possesses a 5-helix bundle core, with unstructured N- and C-terminal regions that account for >50% of the protein sequence. It plays a unique role of interacting with host RNA polymerase, couples transcription with DNA replication, and plays the dual function as repressor and co-activator in phage transcription. Here, we identify protein structural plasticity as the molecular basis of the dual nature in gp33...
August 12, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28805214/the-low-populated-folding-intermediate-of-a-mutant-of-the-fyn-sh3-domain-identified-by-a-simple-model
#4
Jing Wu, Guojun Chen, Zhuqing Zhang, Ping Zhang, Tao Chen
Experimental studies indicate that the A39V/N53P/V55L Fyn SH3 domain folds from the unfolded state to the native state via a low-populated on-pathway intermediate, whereas the folding of the wildtype is two-state-like. To get insights into the biophysical basis of their different folding mechanisms, we used native-centric models with and without additional transferrable, sequence-dependent nonnative hydrophobic interactions to study the folding behaviors of the Fyn SH3 domain and its mutant. The pure native-centric model predicts that both the wildtype and the mutant fold in a two-state manner, without any detectable intermediate...
August 14, 2017: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/28800583/the-nucleoid-protein-dps-binds-genomic-dna-of-escherichia-coli-in-a-non-random-manner
#5
S S Antipov, M N Tutukina, E V Preobrazhenskaya, F A Kondrashov, M V Patrushev, S V Toshchakov, I Dominova, U S Shvyreva, V V Vrublevskaya, O S Morenkov, N A Sukharicheva, V V Panyukov, O N Ozoline
Dps is a multifunctional homododecameric protein that oxidizes Fe2+ ions accumulating them in the form of Fe2O3 within its protein cavity, interacts with DNA tightly condensing bacterial nucleoid upon starvation and performs some other functions. During the last two decades from discovery of this protein, its ferroxidase activity became rather well studied, but the mechanism of Dps interaction with DNA still remains enigmatic. The crucial role of lysine residues in the unstructured N-terminal tails led to the conventional point of view that Dps binds DNA without sequence or structural specificity...
2017: PloS One
https://www.readbyqxmd.com/read/28793213/critical-influence-of-cosolutes-and-surfaces-on-the-assembly-of-serpin-derived-amyloid-fibrils
#6
Michael W Risør, Dennis W Juhl, Morten Bjerring, Joachim Mathiesen, Jan J Enghild, Niels C Nielsen, Daniel E Otzen
Many proteins and peptides self-associate into highly ordered and structurally similar amyloid cross-β aggregates. This fibrillation is critically dependent on properties of the protein and the surrounding environment that alter kinetic and thermodynamic equilibria. Here, we report on dominating surface and solution effects on the fibrillogenic behavior and amyloid assembly of the C-36 peptide, a circulating bioactive peptide from the α1-antitrypsin serine protease inhibitor. C-36 converts from an unstructured peptide to mature amyloid twisted-ribbon fibrils over a few hours when incubated on polystyrene plates under physiological conditions through a pathway dominated by surface-enhanced nucleation...
August 8, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/28767224/iminodiacetic-acid-modified-human-serum-albumin-a-multifunctional-agent-against-metal-associated-amyloid-%C3%AE-protein-aggregation-and-cytotoxicity
#7
Baolong Xie, Huan Zhang, Xi Li, Xiaoyan Dong, Yan Sun
Metal-induced amyloid β-protein (Aβ) aggregation plays a key role in the pathogenesis of Alzheimer's disease. Although several agents have been recognized to block metal-associated Aβ aggregation, their therapeutic potential is marred due to the high-concentration metal ions in the amyloid plaques. To overcome the problem, we have herein developed iminodiacetic acid-modified human serum albumin (I-HSA) to fight against the aggregation. The multifunctional feature of I-HSA was extensively characterized in inhibiting Aβ42 aggregation associated with Zn2+ and Cu2+...
August 2, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28765221/signal-peptide-hydrophobicity-modulates-interaction-with-the-twin-arginine-translocase
#8
Qi Huang, Tracy Palmer
The general secretory pathway (Sec) and twin-arginine translocase (Tat) operate in parallel to export proteins across the cytoplasmic membrane of prokaryotes and the thylakoid membrane of plant chloroplasts. Substrates are targeted to their respective machineries by N-terminal signal peptides that share a tripartite organization; however, Tat signal peptides harbor a conserved and almost invariant arginine pair that is critical for efficient targeting to the Tat machinery. Tat signal peptides interact with a membrane-bound receptor complex comprised of TatB and TatC components, with TatC containing the twin-arginine recognition site...
August 1, 2017: MBio
https://www.readbyqxmd.com/read/28760887/structural-evidence-of-a-phosphoinositide-binding-site-in-the-rgd1-rhogap-domain
#9
Denis Martinez, Béatrice Langlois d'Estaintot, Thierry Granier, James Tolchard, Cécile Courrèges, Valérie Prouzet-Mauléon, Michel Hugues, Bernard Gallois, François Doignon, Benoit Odaert
Phosphoinositide lipids recruit proteins to the plasma membrane involved in the regulation of cytoskeleton organization and in signalling pathways that control cell polarity and growth. Among those, Rgd1p is a yeast GTPase activating protein (GAP) specific for Rho3p and Rho4p GTPases, which control actin polymerization and stress signalling pathways. Phosphoinositides not only bind Rgd1p, but also stimulate its GAP activity on the membrane-anchored form of Rho4p. Both F-BAR and RhoGAP domains of Rgd1p are involved in lipid interactions...
July 31, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28759722/perturbation-in-long-range-contacts-modulates-the-kinetics-of-amyloid-formation-in-%C3%AE-synuclein-familial-mutants
#10
Priyatosh Ranjan, Ashutosh Kumar
The characteristic cross-β-sheet-rich amyloid fibril formation by intrinsically disordered α-synuclein proteins is one of the pathological hallmarks of Parkinson's disease. Although unstructured in solution, the presence of autoinhibitory long-range contacts in monomeric form prevents protein aggregation. Out of the various factors that affect the rate of amyloid formation, familial mutations play an important role in α-synuclein aggregation. Even though these mutations are believed to form an aggregation-prone intermediate by perturbing these contacts, the correlation between perturbation and rate of fibril formation is not very straightforward...
August 14, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28758665/the-length-but-not-the-sequence-of-peptide-linker-modules-exerts-the-primary-influence-on-the-conformations-of-protein-domains-in-cellulosome-multi-enzyme-complexes
#11
Bartosz Różycki, Pierre-André Cazade, Shane O'Mahony, Damien Thompson, Marek Cieplak
Cellulosomes are large multi-protein catalysts produced by various anaerobic microorganisms to efficiently degrade plant cell-wall polysaccharides down into simple sugars. X-ray and physicochemical structural characterisations show that cellulosomes are composed of numerous protein domains that are connected by unstructured polypeptide segments, yet the properties and possible roles of these 'linker' peptides are largely unknown. We have performed coarse-grained and all-atom molecular dynamics computer simulations of a number of cellulosomal linkers of different lengths and compositions...
August 16, 2017: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/28753295/empirical-correction-for-differences-in-chemical-exchange-rates-in-hydrogen-exchange-mass-spectrometry-measurements
#12
Ronald T Toth, Brittney J Mills, Sangeeta B Joshi, Reza Esfandiary, Steven M Bishop, C Russell Middaugh, David B Volkin, David D Weis
A barrier to the use of hydrogen exchange-mass spectrometry (HX-MS) in many contexts, especially analytical characterization of various protein therapeutic candidates, is that differences in temperature, pH, ionic strength, buffering agent, or other additives can alter chemical exchange rates, making HX data gathered under differing solution conditions difficult to compare. Here, we present data demonstrating that HX chemical exchange rates can be substantially altered not only by the well-established variables of temperature and pH but also by additives including arginine, guanidine, methionine, and thiocyanate...
August 11, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28750009/mrna-protein-sequence-complementarity-and-its-determinants-the-impact-of-affinity-scales
#13
Lukas Bartonek, Bojan Zagrovic
It has recently been demonstrated that the nucleobase-density profiles of mRNA coding sequences are related in a complementary manner to the nucleobase-affinity profiles of their cognate protein sequences. Based on this, it has been proposed that cognate mRNA/protein pairs may bind in a co-aligned manner, especially if unstructured. Here, we study the dependence of mRNA/protein sequence complementarity on the properties of the nucleobase/amino-acid affinity scales used. Specifically, we sample the space of randomly generated scales by employing a Monte Carlo strategy with a fitness function that depends directly on the level of complementarity...
July 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/28745031/a-tale-of-two-tails-the-importance-of-unstructured-termini-in-the-aggregation-pathway-of-%C3%AE-2-microglobulin
#14
Rui J S Loureiro, Diogo Vila-Viçosa, Miguel Machuqueiro, Eugene I Shakhnovich, Patricia F N Faísca
The identification of intermediate states for folding and aggregation is important from a fundamental standpoint and for the design of novel therapeutic strategies targeted at conformational disorders. Protein human β2-microglobulin (HB2m) is classically associated with dialysis-related amyloidosis, but the single point mutant D76N was recently identified as the causative agent of a hereditary systemic amyloidosis affecting visceral organs. Here, we use D76N as a model system to explore the early stage of the aggregation mechanism of HB2m by means of an integrative approach framed on molecular simulations...
July 26, 2017: Proteins
https://www.readbyqxmd.com/read/28733487/the-stat4-mll1-epigenetic-axis-regulates-the-antimicrobial-functions-of-murine-macrophages
#15
William F Carson, Karen A Cavassani, Elyara M Soares, Soichiro Hirai, Nicolai A Kittan, Matthew A Schaller, Melissa M Scola, Amrita Joshi, Akihiro Matsukawa, David M Aronoff, Craig N Johnson, Yali Dou, Katherine A Gallagher, Steven L Kunkel
Macrophages are critical immune cells for the clearance of microbial pathogens and cellular debris from peripheral tissues. Macrophage inflammatory responses are governed by gene expression patterns, and these patterns are often subject to epigenetic control. Chromatin modifications, such as histone methylation, regulate gene accessibility in macrophages, and macrophage polarization is governed in part by the expression and function of chromatin-modifying enzymes. The histone methyltransferase mixed-lineage leukemia 1 (MLL1) preferentially modifies lysine residue 4 on the unstructured protein tail of histone H3...
September 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28725901/zinc-binding-sites-in-pra1-a-zincophore-from-candida-albicans
#16
Dorota Łoboda, Magdalena Rowińska-Żyrek
The aim of this work is to understand the interactions of Zn(ii) with Pra1, a zincophore from Candida albicans, one of the most common causes of serious fungal infections in humans. Pra1 is a 299 amino acid protein, secreted from the fungus to specifically bind Zn(ii) and deliver it to a transmembrane zinc transporter, Zrt1. We take the first step towards understanding the bioinorganic chemistry of this process, by pointing out the Zn(ii) binding sites in Pra1 and understanding the thermodynamics of such interactions...
July 20, 2017: Dalton Transactions: An International Journal of Inorganic Chemistry
https://www.readbyqxmd.com/read/28723106/proteins-breaking-bad-a-free-energy-perspective
#17
Jessica Valle-Orero, Rafael Tapia-Rojo, Edward C Eckels, Jaime Andrés Rivas-Pardo, Ionel Popa, Julio M Fernández
Protein aging may manifest as a mechanical disease that compromises tissue elasticity. As proved recently, while proteins respond to changes in force with an instantaneous elastic recoil followed by a folding contraction, aged proteins break bad, becoming unstructured polymers. Here, we explain this phenomenon in the context of a free energy model, predicting the changes in the folding landscape of proteins upon oxidative aging. Our findings validate that protein folding under force is constituted by two separable components, polymer properties and hydrophobic collapse, and demonstrate that the latter becomes irreversibly blocked by oxidative damage...
July 25, 2017: Journal of Physical Chemistry Letters
https://www.readbyqxmd.com/read/28722139/structure-based-release-analysis-of-the-jc-virus-agnoprotein-regions-a-role-for-the-hydrophilic-surface-of-the-major-alpha-helix-domain-in-release
#18
A Sami Saribas, Martyn K White, Mahmut Safak
Agnoprotein (Agno) is an important regulatory protein of JC virus (JCV), BK virus (BKV) and simian virus 40 (SV40) and these viruses are unable to replicate efficiently in the absence of this protein. Recent 3D-NMR structural data revealed that Agno contains two alpha-helices (a minor and a major) while the rest of the protein adopts an unstructured conformation (Coric et al., 2017, J Cell Biochem). Previously, release of the JCV Agno from the Agno-positive cells was reported. Here, we have further mapped the regions of Agno responsible for its release by a structure-based systematic mutagenesis approach...
July 19, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28714684/the-surface-of-protein-%C3%AE-6-85-can-act-as-a-template-for-recurring-peg-structure
#19
Shu-Han Chao, Jan Schaefer, Martin Gruebele
PEGylated proteins play an increasingly important role in pharmaceutical drug delivery. We recently showed that short PEG chains can affect protein structure, even when they are not making extensive contact with the protein surface. In contrast, PEG is generally assumed to form a relatively unstructured coil, whose compactness depends on solvent conditions. Here we test whether a host protein could allow PEG to form recurrent structural motifs while the PEG chain is in contact with the protein surface. We link a PEG oligomer (n=45) to one of two nearly opposite locations on the small alpha-helical protein 6-85 to investigate this question...
July 17, 2017: Biochemistry
https://www.readbyqxmd.com/read/28712389/rescuing-p53-from-mdm2-by-intrinsically-unfolded-sumo-protease-4
#20
Do-Hyoung Kim, Chewook Lee, Bom Kim, Si-Hyung Lee, Kyou-Hoon Han
Many intrinsically unstructured/unfolded proteins (IUPs) contain transient local secondary structures even though they are "unstructured" in a tertiary sense. These local secondary structures are named "pre-structured motifs (PreSMos)" and in fact are the specificity determinants for IUP-target binding, i.e., the active sites in IUPs. Using high-resolution NMR we have delineated a PreSMo active site in the intrinsically unfolded mid-domain (residues 201-300) of SUMO-specific protease 4 (SUSP4). This 29-residue motif which we termed a p53 rescue motif can protect p53 from mdm2 quenching by binding to the p53-helix binding pocket in mdm2(3-109)...
July 17, 2017: BMB Reports
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