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https://www.readbyqxmd.com/read/28332566/a-conformational-change-within-the-wave2-complex-regulates-its-degradation-following-cellular-activation
#1
Noah Joseph, Guy Biber, Sophia Fried, Barak Reicher, Omer Levy, Batel Sabag, Elad Noy, Mira Barda-Saad
WASp family Verprolin-homologous protein-2 (WAVE2), a member of the Wiskott-Aldrich syndrome protein (WASp) family of actin nucleation promoting factors, is a central regulator of actin cytoskeleton polymerization and dynamics. Multiple signaling pathways operate via WAVE2 to promote the actin-nucleating activity of the actin-related protein 2/3 (Arp2/3) complex. WAVE2 exists as a part of a pentameric protein complex known as the WAVE regulatory complex (WRC), which is unstable in the absence of its individual proteins...
March 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28302907/skip-controls-lysosome-positioning-using-a-composite-kinesin-1-heavy-and-light-chain-binding-domain
#2
Anneri Sanger, Yan Y Yip, Thomas S Randall, Stefano Pernigo, Roberto A Steiner, Mark P Dodding
The molecular interplay between cargo recognition and regulation of the activity of the kinesin-1 microtubule motor is not well understood. Using the lysosome adaptor SKIP as model cargo, we show that the heavy chains (KHCs), in addition to the light chains (KLCs), can recognize tryptophan-acidic binding determinants on the cargo when presented in the context of an extended KHC interacting domain. Mutational separation of KHC and KLC binding shows that both interactions are important for SKIP-kinesin-1 interaction in vitro and that KHC binding is important for lysosome transport in vivo...
March 16, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28295333/calmodulin-kinases-essential-regulators-in-health-and-disease
#3
REVIEW
Sayaka Takemoto-Kimura, Kanzo Suzuki, Shin-Ichiro Horigane, Satoshi Kamijo, Masatoshi Inoue, Masayuki Sakamoto, Hajime Fujii, Haruhiko Bito
Neuronal activity induces intracellular Ca(2+) increase, which triggers activation of a series of Ca(2+) -dependent signalling cascades. Among these, the multifunctional Ca(2+) / calmodulin-dependent protein kinases (CaMKs, or calmodulin kinases) play key roles in neuronal transmission, synaptic plasticity, circuit development and cognition. The most investigated CaMKs for these roles in neuronal functions are CaMKI, CaMKII, CaMKIV and we will shed light on these neuronal CaMKs' functions in this review. Catalytically active members of CaMKs currently are CaMKI, CaMKII, CaMKIV and CaMKK...
March 15, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28289209/injury-stimulated-and-self-restrained-bmp-signaling-dynamically-regulates-stem-cell-pool-size-during-drosophila-midgut-regeneration
#4
Aiguo Tian, Bing Wang, Jin Jiang
Many adult organs rely on resident stem cells to maintain homeostasis. Upon injury, stem cells increase proliferation, followed by lineage differentiation to replenish damaged cells. Whether stem cells also change division mode to transiently increase their population size as part of a regenerative program and, if so, what the underlying mechanism is have remained largely unexplored. Here we show that injury stimulates the production of two bone morphogenetic protein (BMP) ligands, Dpp and Gbb, which drive an expansion of intestinal stem cells (ISCs) by promoting their symmetric self-renewing division in Drosophila adult midgut...
March 13, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28264982/dopamine-inhibition-differentially-controls-excitability-of-snc-dopamine-neuron-subpopulations-through-recruitment-of-t-type-calcium-channels
#5
Rebekah C Evans, Manhua Zhu, Zayd M Khaliq
While there is growing appreciation for diversity among ventral tegmental area (VTA) dopamine neurons, much less is known regarding functional heterogeneity among substantia nigra (SNc) neurons. Here, we show that calbindin-positive dorsal tier and calbindin-negative ventral tier SNc dopaminergic neurons in mice comprise functionally distinct subpopulations distinguished by their dendritic calcium signaling, rebound excitation, and physiological responses to dopamine D2-receptor (D2) autoinhibition. While dopamine is known to inhibit action potential backpropagation, our experiments revealed an unexpected enhancement of excitatory responses and dendritic calcium signals in the presence of D2-receptor inhibition...
March 6, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28258142/activation-mechanism-and-cellular-localization-of-membrane-anchored-alginate-polymerase-in-pseudomonas-aeruginosa
#6
M Fata Moradali, Shirin Ghods, Bernd H A Rehm
The exopolysaccharide, alginate, produced by the opportunistic human pathogen Pseudomonas aeruginosa represents a survival advantage by contributing to formation of characteristic biofilms during infection. Membrane anchored proteins Alg8 (catalytic subunit) and Alg44 (co-polymerase) constitute the alginate polymerase which is being activated by the second messenger molecule c-di-GMP, but the mechanism of activation remains elusive. To shed light on the c-di-GMP mediated activation of alginate polymerization in vivo, an in silico structural model of Alg8 fused to the c-di-GMP binding PilZ domain informed by the structure of cellulose synthase, BcsA, was developed...
March 3, 2017: Applied and Environmental Microbiology
https://www.readbyqxmd.com/read/28251751/histone-h1-chaperone-activity-of-taf-i-is-regulated-by-its-subtype-dependent-intramolecular-interaction
#7
Kaori Kajitani, Kohsuke Kato, Kyosuke Nagata
Linker histone H1 is involved in the regulation of gene activity through the maintenance of higher-order chromatin structure. Previously, we have shown that template activating factor-I (TAF-I or protein SET) is involved in linker histone H1 dynamics as a histone H1 chaperone. In human and murine cells, two TAF-I subtypes exist, namely TAF-Iα and TAF-Iβ. TAF-I has a highly acidic amino acid cluster in its C-terminal region and forms homo- or heterodimers through its dimerization domain. Both dimer formation and the C-terminal region of TAF-I are essential for the histone chaperone activity...
March 2, 2017: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
https://www.readbyqxmd.com/read/28242696/structural-basis-of-autoregulatory-scaffolding-by-apoptosis-signal-regulating-kinase-1
#8
Johannes F Weijman, Abhishek Kumar, Sam A Jamieson, Chontelle M King, Tom T Caradoc-Davies, Elizabeth C Ledgerwood, James M Murphy, Peter D Mace
Apoptosis signal-regulating kinases (ASK1-3) are apical kinases of the p38 and JNK MAP kinase pathways. They are activated by diverse stress stimuli, including reactive oxygen species, cytokines, and osmotic stress; however, a molecular understanding of how ASK proteins are controlled remains obscure. Here, we report a biochemical analysis of the ASK1 kinase domain in conjunction with its N-terminal thioredoxin-binding domain, along with a central regulatory region that links the two. We show that in solution the central regulatory region mediates a compact arrangement of the kinase and thioredoxin-binding domains and the central regulatory region actively primes MKK6, a key ASK1 substrate, for phosphorylation...
February 27, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28231333/molecular-mechanisms-of-cooperative-binding-of-transcription-factors-runx1-cbf%C3%AE-ets1-on-the-tcr%C3%AE-gene-enhancer
#9
Kota Kasahara, Masaaki Shiina, Ikuo Fukuda, Kazuhiro Ogata, Haruki Nakamura
Ets1 is an essential transcription factor (TF) for several important physiological processes, including cell proliferation and differentiation. Its recognition of the enhancer region of the TCRα gene is enhanced by the cooperative binding of the Runx1-CBFβ heterodimer, with the cancelation of phosphorylation-dependent autoinhibition. The detailed mechanism of this interesting cooperativity between Ets1 and the Runx1-CBFβ heterodimer is still largely unclear. Here, we investigated the molecular mechanisms of this cooperativity, by using molecular dynamics simulations...
2017: PloS One
https://www.readbyqxmd.com/read/28228524/structural-insights-into-the-activation-mechanism-of-dynamin-like-ehd-atpases
#10
Arthur Alves Melo, Balachandra G Hegde, Claudio Shah, Elin Larsson, J Mario Isas, Séverine Kunz, Richard Lundmark, Ralf Langen, Oliver Daumke
Eps15 (epidermal growth factor receptor pathway substrate 15)-homology domain containing proteins (EHDs) comprise a family of dynamin-related mechano-chemical ATPases involved in cellular membrane trafficking. Previous studies have revealed the structure of the EHD2 dimer, but the molecular mechanisms of membrane recruitment and assembly have remained obscure. Here, we determined the crystal structure of an amino-terminally truncated EHD4 dimer. Compared with the EHD2 structure, the helical domains are 50° rotated relative to the GTPase domain...
February 22, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28223496/ehd2-restrains-dynamics-of-caveolae-by-an-atp-dependent-membrane-bound-open-conformation
#11
Maria Hoernke, Jagan Mohan, Elin Larsson, Jeanette Blomberg, Dana Kahra, Sebastian Westenhoff, Christian Schwieger, Richard Lundmark
The EH-domain-containing protein 2 (EHD2) is a dynamin-related ATPase that confines caveolae to the cell surface by restricting the scission and subsequent endocytosis of these membrane pits. For this, EHD2 is thought to first bind to the membrane, then to oligomerize, and finally to detach, in a stringently regulated mechanistic cycle. It is still unclear how ATP is used in this process and whether membrane binding is coupled to conformational changes in the protein. Here, we show that the regulatory N-terminal residues and the EH domain keep the EHD2 dimer in an autoinhibited conformation in solution...
February 21, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28222177/phospholipid-binding-to-the-fak-catalytic-domain-impacts-function
#12
Jessica E Hall, Michael D Schaller
Focal adhesion kinase is an essential nonreceptor tyrosine kinase that plays an important role in development, in homeostasis and in the progression of human disease. Multiple stimuli activate FAK, which requires a change in structure from an autoinhibited to activated conformation. In the autoinhibited conformation the FERM domain associates with the catalytic domain of FAK and PI(4,5)P2 binding to the FERM domain plays a role in the release of autoinhibition, activating the enzyme. An in silico model of FAK/PI(4,5)P2 interaction suggests that residues on the catalytic domain interact with PI(4,5)P2, in addition to the known FERM domain PI(4,5)P2 binding site...
2017: PloS One
https://www.readbyqxmd.com/read/28199769/protein-templated-formation-of-an-inhibitor-of-the-blood-coagulation-factor%C3%A2-xa-through-a-background-free-amidation-reaction
#13
Mike Jaegle, Torsten Steinmetzer, Jörg Rademann
Protein-templated reactions enable the target-guided formation of protein ligands from reactive fragments, ideally with no background reaction. Herein, we investigate the templated formation of amides. A nucleophilic fragment that binds to the coagulation factor Xa was incubated with the protein and thirteen differentially activated dipeptides. The protein induced a non-catalytic templated reaction for the phenyl and trifluoroethyl esters; the latter was shown to be a completely background-free reaction. Starting from two fragments with millimolar affinity, a 29 nm superadditive inhibitor of factor Xa was obtained...
February 15, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28197608/the-dynamic-mechanism-of-rassf5-and-mst-kinase-activation-by-ras
#14
Tsung-Jen Liao, Hyunbum Jang, Chung-Jung Tsai, David Fushman, Ruth Nussinov
As a tumor suppressor, RASSF5 (NORE1A) activates MST1/2 thereby modulating the Hippo pathway. Structurally, activation involves RASSF5 and MST1/2 swapping their SARAH domains to form a SARAH heterodimer. This exposes the MST1/2 kinase domain which homodimerizes, leading to trans-autophosphorylation. The SARAH-SARAH interaction shifts RASSF5 away from its autoinhibited state and relieves MST1/2 autoinhibition. Separate crystal structures are available for the RA (Ras association) domain and SARAH dimer, where SARAH is a long straight α-helix...
February 15, 2017: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/28196833/characterization-of-the-activation-of-small-gtpases-by-their-gefs-on-membranes-using-artificial-membrane-tethering
#15
François Peurois, Simon Veyron, Yann Ferrandez, Ilham Ladid, Sarah Benabdi, Mahel Zeghouf, Gérald Peyroche, Jacqueline Cherfils
Attachment of active, GTP-bound small GTPases to membranes by post-translational lipid modifications is pivotal for their ability to process and propagate information in cells. However, generating and manipulating lipidated GTPases has remained difficult, which has limited our quantitative understanding of their activation by GEFs and their termination by GAPs. Here we replaced the lipid modification by a histidine tag in eleven full-length, human small GTPases belonging to the Arf, Rho and Rab families, which allowed to tether them to nickel-lipid containing membranes and characterize the kinetics of their activation by GEFs...
February 14, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28166054/elucidation-of-a-four-site-allosteric-network-in-fibroblast-growth-factor-receptor-tyrosine-kinases
#16
Huaibin Chen, William M Marsiglia, Min-Kyu Cho, Zhifeng Huang, Jingjing Deng, Steven P Blais, Weiming Gai, Shibani Bhattacharya, Thomas A Neubert, Nathaniel J Traaseth, Moosa Mohammadi
Receptor tyrosine kinase (RTK) signaling is tightly regulated by protein allostery within the intracellular tyrosine kinase domains. Yet the molecular determinants of allosteric connectivity in tyrosine kinase domain are incompletely understood. By means of structural (X-ray and NMR) and functional characterization of pathogenic gain-of-function mutations affecting the FGF receptor (FGFR) tyrosine kinase domain, we elucidated a long-distance allosteric network composed of four interconnected sites termed the 'molecular brake', 'DFG latch', 'A-loop plug', and 'αC tether'...
February 6, 2017: ELife
https://www.readbyqxmd.com/read/28161714/structured-and-disordered-regions-cooperatively-mediate-dna-binding-autoinhibition-of-ets-factors-etv1-etv4-and-etv5
#17
Simon L Currie, Desmond K W Lau, Jedediah J Doane, Frank G Whitby, Mark Okon, Lawrence P McIntosh, Barbara J Graves
No abstract text is available yet for this article.
February 6, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28160000/engineering-carboxypeptidase-g2-circular-permutations-for-the-design-of-an-autoinhibited-enzyme
#18
Brahm J Yachnin, Sagar D Khare
No abstract text is available yet for this article.
February 4, 2017: Protein Engineering, Design & Selection: PEDS
https://www.readbyqxmd.com/read/28159798/destabilizing-the-autoinhibitory-conformation-of-zap70-induces-up-regulation-of-inhibitory-receptors-and-t-cell-unresponsiveness
#19
Lih-Yun Hsu, Debra A Cheng, Yiling Chen, Hong-Erh Liang, Arthur Weiss
Zap70 plays a critical role in normal T cell development and T cell function. However, little is known about how perturbation of allosteric autoinhibitory mechanisms in Zap70 impacts T cell biology. Here, we analyze mice with a hypermorphic Zap70 mutation, W131A, which destabilizes the autoinhibitory conformation of Zap70, rendering the kinase in a semiactive state. W131A mutant mice with wild-type T cell receptor (TCR) repertoires exhibited relatively normal T cell development. However, crossing the W131A mutant mice to OTII TCR transgenic mice resulted in increased negative selection of OTII(+) thymocytes and in increased thymic and peripheral T regulatory cells...
March 6, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28124908/structural-insights-how-pip2-imposes-preferred-binding-orientations-of-fak-at-lipid-membranes
#20
Florian A Herzog, Lukas Braun, Ingmar Schoen, Viola Vogel
Focal adhesion kinase (FAK) is a multidomain protein (FERM-kinase-FAT) with important signaling functions in the regulation of cell-substrate adhesions. Its inactive, autoinhibited form is recruited from the cytoplasm to the plasma membrane, where it becomes activated at PIP2 enriched regions. To elucidate the molecular basis of activation, we performed a systematic screening of binding orientations of FAK's autoinhibited FERM-kinase complex, as well as of the dissociated FERM and kinase domains alone, on model plasma membranes using coarse-grained scFix MARTINI simulations, partially corroborated by atomistic MD simulations...
February 10, 2017: Journal of Physical Chemistry. B
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