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Lakshmi Maganti, Sutapa Dutta, Mahua Ghosh, J Chakrabarti
Here we study microscopic mechanism of complex formation between Ca2+ bound -calmodulin (holoCaM) and Orai1 that regulates Ca2+-dependent inactivation process in eukaryotic cells. We compute conformational thermodynamic changes in holoCaM with respect to complex of Orai1 bound to C-terminal domain of holoCaM using histograms of dihedral angles of the proteins over trajectories from molecular dynamics simulations. Our analysis shows that the N-terminal domain residues L4, T5, Q41, N42, T44 and E67 of holoCaM get destabilized and disordered due to Orai1 binding to C-terminal domain of calmodulin affect the N-terminal domain residues...
January 18, 2018: Journal of Biomolecular Structure & Dynamics
Varnavas D Mouchlis, Yuan Chen, J Andrew McCammon, Edward A Dennis
We demonstrate that lipidomics coupled with molecular dynamics reveals unique phospholipase A2 specificity toward membrane phospholipid substrates. We discovered unexpected head-group and acyl-chain specificity for three-major human phospholipases A2. These differences between each enzyme's specificity coupled with molecular dynamicsbased structural and binding studies revealed unique active site and interfacial surface binding moieties for each enzyme that explains the observed specificity at a hitherto inaccessible structural level...
January 17, 2018: Journal of the American Chemical Society
Xiao Yan, Qiaoyun Shi, Andreas Bracher, Goran Miličić, Amit K Singh, F Ulrich Hartl, Manajit Hayer-Hartl
The bacterial chaperonin GroEL and its cofactor, GroES, form a nano-cage for a single molecule of substrate protein (SP) to fold in isolation. GroEL and GroES undergo an ATP-regulated interaction cycle to close and open the folding cage. GroEL consists of two heptameric rings stacked back to back. Here, we show that GroEL undergoes transient ring separation, resulting in ring exchange between complexes. Ring separation occurs upon ATP-binding to the trans ring of the asymmetric GroEL:7ADP:GroES complex in the presence or absence of SP and is a consequence of inter-ring negative allostery...
December 26, 2017: Cell
Andrew F Neuwald, L Aravind, Stephen F Altschul
Residues responsible for allostery, cooperativity, and other subtle but functionally important interactions remain difficult to detect. To aid such detection, we employ statistical inference based on the assumption that residues distinguishing a protein subgroup from evolutionarily divergent subgroups often constitute an interacting functional network. We identify such networks with the aid of two measures of statistical significance. One measure aids identification of divergent subgroups based on distinguishing residue patterns...
January 16, 2018: ELife
Melis Kayikci, A J Venkatakrishnan, James Scott-Brown, Charles N J Ravarani, Tilman Flock, M Madan Babu
Visualizations of biomolecular structures empower us to gain insights into biological functions, generate testable hypotheses, and communicate biological concepts. Typical visualizations (such as ball and stick) primarily depict covalent bonds. In contrast, non-covalent contacts between atoms, which govern normal physiology, pathogenesis, and drug action, are seldom visualized. We present the Protein Contacts Atlas, an interactive resource of non-covalent contacts from over 100,000 PDB crystal structures. We developed multiple representations for visualization and analysis of non-covalent contacts at different scales of organization: atoms, residues, secondary structure, subunits, and entire complexes...
January 15, 2018: Nature Structural & Molecular Biology
Lena Simine, Heiko Lammert, Li Sun, Jose Nelson Onuchic, Peter J Rossky
The rational design of genetically encoded fluorescent bio-sensors, which can detect rearrangements of target proteins via interdomain allostery, is hindered by the absence of mechanistic understanding of the underlying photo-physics. Here, we focus on the modulation of fluorescence by mechanical perturbation in a popular biological probe: enhanced Green Fluorescent Protein (eGFP). Using a combination of molecular dynamics (MD) simulations and quantum chemistry, and a set of physically motivated assumptions, we construct a map of fluorescence quantum yield as a function of a 2D electric field imposed by the protein environment on the fluorophore...
January 12, 2018: Journal of the American Chemical Society
Brooke E Husic, Vijay S Pande
Markov state models (MSMs) are a powerful framework for analyzing dynamical systems, such as molecular dynamics (MD) simulations, that have gained widespread use over the past several decades. This review offers a complete picture of the MSM field to date, presented for a general audience as a timeline of key developments in the field. We sequentially address early studies that motivated the method, canonical papers that established the use of MSMs for MD analysis, and subsequent advances in software and analysis protocols...
January 11, 2018: Journal of the American Chemical Society
Brendan J Mahoney, Meiling Zhang, John S Zintsmaster, Jeffrey W Peng
Pin1 is a two-domain human protein that catalyzes the cis-trans isomerization of pSer/pThr-Pro (pS/T-P) motifs in numerous cell cycle regulatory proteins. These pS/T-P motifs bind to Pin1's peptidyl-prolyl isomerase (PPIase) domain in a catalytic pocket, between an extended catalytic loop and the PPIase domain core. Previous studies showed that post-translational phosphorylation of S71 in the catalytic loop decreases substrate binding affinity and isomerase activity. To define the origins for these effects, we investigated a phosphomimetic Pin1 mutant, S71E-Pin1, using solution nuclear magnetic resonance (NMR)...
January 6, 2018: Journal of Molecular Biology
Damian Bartuzi, Agnieszka A Kaczor, Dariusz Matosiuk
Allostery is one of the most important features of proteins. It greatly contributes to the complexity of life, since it enables possibility of precise tuning of protein function, as well as performing more than one function per protein. Probe dependence is one of unique features of allostery. It allows a protein to respond differently to the same allosteric modulator when different drugs or transmitters are bound. Unfortunately, allosteric mechanisms are difficult to investigate experimentally. Instead, they can be reproduced artificially in simulations...
December 14, 2017: Journal of Biomolecular Structure & Dynamics
Srivatsan Raman
The study of allostery has a central place in biology due to the myriad roles of allosteric proteins in cellular function. As technologies to probe spatiotemporal resolution of biomolecules have become increasingly sophisticated, so has our understanding of the diverse structural and molecular mechanisms of allosteric proteins. Studies have shown that allosteric signal is transmitted a through a network of residue-residue interactions connecting distal sites on a protein. Linking structural and dynamical changes to the functional role of individual residues will give a more complete molecular view of allostery...
December 13, 2017: Biochemistry
Deborah K Shoemark, Richard B Sessions, Andrea Brancaccio, Maria Giulia Bigotti
Class II chaperonins are essential multisubunit complexes that aid the folding of nonnative proteins in the cytosol of archaea and eukarya. They use energy derived from ATP to drive a series of structural rearrangements that enable polypeptides to fold within their central cavity. These events are regulated by an elaborate allosteric mechanism in need of elucidation. We employed mutagenesis and experimental analysis in concert with in silico molecular dynamics simulations and interface-binding energy calculations to investigate the class II chaperonin from Thermoplasma acidophilum Here we describe the effects on the asymmetric allosteric mechanism and on hetero-oligomeric complex formation in a panel of mutants in the ATP-binding pocket of the α and β subunits...
December 12, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Kelly M Thayer, Jesse C Galganov, Avram J Stein
Allostery is a regulatory mechanism in proteins where an effector molecule binds distal from an active site to modulate its activity. Allosteric signaling may occur via a continuous path of residues linking the active and allosteric sites, which has been suggested by large conformational changes evident in crystal structures. An alternate possibility is that the signal occurs in the realm of ensemble dynamics via an energy landscape change. While the latter was first proposed on theoretical grounds, increasing evidence suggests that such a control mechanism is plausible...
2017: PloS One
Takato Sato, Jun Ohnuki, Mitsunori Takano
A protein molecule is a dielectric substance, so the binding of a ligand is expected to induce dielectric response in the protein molecule, considering that ligands are charged or polar in general. We previously reported that binding of adenosine triphosphate (ATP) to molecular motor myosin actually induces such a dielectric response in myosin due to the net negative charge of ATP. By this dielectric response, referred to as "dielectric allostery," spatially separated two regions in myosin, the ATP-binding region and the actin-binding region, are allosterically coupled...
December 7, 2017: Journal of Chemical Physics
Hari R Singh, Aurelio P Nardozza, Ingvar R Möller, Gunnar Knobloch, Hans A V Kistemaker, Markus Hassler, Nadine Harrer, Charlotte Blessing, Sebastian Eustermann, Christiane Kotthoff, Sébastien Huet, Felix Mueller-Planitz, Dmitri V Filippov, Gyula Timinszky, Kasper D Rand, Andreas G Ladurner
DNA damage triggers chromatin remodeling by mechanisms that are poorly understood. The oncogene and chromatin remodeler ALC1/CHD1L massively decompacts chromatin in vivo yet is inactive prior to DNA-damage-mediated PARP1 induction. We show that the interaction of the ALC1 macrodomain with the ATPase module mediates auto-inhibition. PARP1 activation suppresses this inhibitory interaction. Crucially, release from auto-inhibition requires a poly-ADP-ribose (PAR) binding macrodomain. We identify tri-ADP-ribose as a potent PAR-mimic and synthetic allosteric effector that abrogates ATPase-macrodomain interactions, promotes an ungated conformation, and activates the remodeler's ATPase...
December 7, 2017: Molecular Cell
Jacqueline Cherfils
In this issue of Molecular Cell, Su et al. (2017) describe the structure of the Rag/Ragulator complex, a key relay in nutrient sensing by mTOR. The structure sheds new light on how signals are conveyed from the lysosome to mTOR.
December 7, 2017: Molecular Cell
Kenneth P Lloyd, Ogooluwa A Ojelabi, Andrew H Simon, Julie K De Zutter, Anthony Carruthers
A growing body of evidence demonstrates that GLUT1-mediated erythrocyte sugar transport is more complex than widely assumed and that contemporary interpretations of emergent GLUT1 structural data are incompatible with the available transport and biochemical data. This study examines the kinetic basis of one such incompatibility-transport allostery-and in doing so suggests how the results of studies examining GLUT1 structure and function may be reconciled. Three types of allostery are observed in GLUT1-mediated, human erythrocyte sugar transport: (1) exofacial cis-allostery in which low concentrations of extracellular inhibitors stimulate sugar uptake while high concentrations inhibit transport; (2) endofacial cis-allostery in which low concentrations of intracellular inhibitors enhance cytochalasin B binding to GLUT1 while high concentrations inhibit binding, and (3) trans-allostery in which low concentrations of ligands acting at one cell surface stimulate ligand binding at or sugar transport from the other surface while high concentrations inhibit these processes...
December 5, 2017: Journal of Membrane Biology
Tomoya Okamoto, Hiroshi Yamamoto, Ikuru Kudo, Kazuya Matsumoto, Masafumi Odaka, Ewa Grave, Hideaki Itoh
The mammalian molecular chaperone, HSP60, plays an essential role in protein homeostasis through mediating protein folding and assembly. The structure and ATP-dependent function of HSP60 has been well established in recent studies. After ATP, GTP is the major cellular nucleotide. In this paper, we have investigated the role of GTP in the activity of HSP60. It was found that HSP60 has different properties with respect to allostery, complex formation and protein folding activity depending on the nucleoside triphosphate present...
December 5, 2017: Scientific Reports
Adam R Offenbacher, Anthony T Iavarone, Judith P Klinman
In lipoxygenases, the topologically conserved C-terminal domain catalyzes the oxidation of polyunsaturated fatty acids, generating an assortment of biologically relevant signaling mediators. Plant and animal lipoxygenases also contain a 100-150 amino acid N-terminal C2-like domain that has been implicated in interactions with isolated fatty acids and at the phospholipid bilayer. These interactions may lead to increased substrate availability and contribute to the regulation of active site catalysis. Because of a lack of structural information, a molecular understanding of this lipid/protein interaction remains unresolved...
November 30, 2017: Journal of Biological Chemistry
Damian Bartuzi, Agnieszka A Kaczor, Dariusz Matosiuk
From the pharmacological point of view, allosteric modulators may present numerous advantages over orthosteric ligands. Growing availability of novel tools and experimental data provides a tempting opportunity to apply computational methods to improve known modulators and design novel ones. However, recent progress in understanding of complexity of allostery increases awareness of problems involved in design of modulators with desired properties. Deeper insight into phenomena such as probe dependence, altering signaling bias with minor changes in ligand structure, as well as influence of subtle endogenous allosteric factors turns out to be fundamental...
2018: Methods in Molecular Biology
William Y C Huang, Jonathon A Ditlev, Han-Kuei Chiang, Michael K Rosen, Jay T Groves
Tyrosine phosphorylation of membrane receptors and scaffold proteins followed by recruitment of SH2 domain-containing adaptor proteins constitutes a central mechanism of intracellular signal transduction. During early T-cell receptor (TCR) activation, phosphorylation of linker for activation of T cells (LAT) leading to recruitment of adaptor proteins, including Grb2, is one prototypical example. LAT contains multiple modifiable sites, and this multivalency may provide additional layers of regulation, although this is not well understood...
November 28, 2017: Journal of the American Chemical Society
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