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https://www.readbyqxmd.com/read/27899597/thermotoga-maritima-nusg-domain-interaction-mediates-autoinhibition-and-thermostability
#1
Johanna Drögemüller, Christin Schneider, Kristian Schweimer, Martin Strauß, Birgitta M Wöhrl, Paul Rösch, Stefan H Knauer
NusG, the only universally conserved transcription factor, comprises an N- and a C-terminal domain (NTD, CTD) that are flexibly connected and move independently in Escherichia coli and other organisms. In NusG from the hyperthermophilic bacterium Thermotoga maritima (tmNusG), however, NTD and CTD interact tightly. This closed state stabilizes the CTD, but masks the binding sites for the interaction partners Rho, NusE and RNA polymerase (RNAP), suggesting that tmNusG is autoinhibited. Furthermore, tmNusG and some other bacterial NusGs have an additional domain, DII, of unknown function...
November 29, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27890928/identification-and-characterization-of-activating-abl1-1b-kinase-mutations-impact-on-sensitivity-to-atp-competitive-and-allosteric-abl1-inhibitors
#2
B J Lee, N P Shah
While pathologically activated ABL1 fusion kinases represent well-validated therapeutic targets, tumor genomic sequencing has identified numerous point mutations in the ABL1 proto-oncogene of unclear significance. Here we describe nine novel ABL1 1b point mutations, including two from clinical isolates, that cause constitutive kinase activation and cellular transformation. All mutants retained sensitivity to ATP-competitive tyrosine kinase inhibitors (TKIs). Several substitutions cluster near the myristoyl-binding pocket, the target of ABL001, a novel clinically active allosteric kinase inhibitor that mimics the autoinhibitory myristoyl group, and likely activate the kinase by relieving physiologic autoinhibition...
November 28, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27881679/the-shigella-virulence-factor-icsa-relieves-n-wasp-autoinhibition-by-displacing-the-vca-domain
#3
Rui P M Mauricio, Cy M Jeffries, Dmitri I Svergun, Janet E Deane
Shigella flexneri is a bacterial pathogen that invades cells of the gastrointestinal tract causing severe dysentery. Shigella mediate intracellular motility and spreading via actin comet tail formation. This process is dependent on the surface-exposed, membrane-embedded virulence factor IcsA, which recruits the host actin regulator N-WASP. Although it is clear that Shigella require N-WASP for this process, the molecular details of this interaction and the mechanism of N-WASP activation remain poorly understood...
November 23, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27881300/structure-of-the-mind-complex-defines-a-regulatory-focus-for-yeast-kinetochore-assembly
#4
Yoana N Dimitrova, Simon Jenni, Roberto Valverde, Yadana Khin, Stephen C Harrison
Kinetochores connect centromeric nucleosomes with mitotic-spindle microtubules through conserved, cross-interacting protein subassemblies. In budding yeast, the heterotetrameric MIND complex (Mtw1, Nnf1, Nsl1, Dsn1), ortholog of the metazoan Mis12 complex, joins the centromere-proximal components, Mif2 and COMA, with the principal microtubule-binding component, the Ndc80 complex (Ndc80C). We report the crystal structure of Kluyveromyces lactis MIND and examine its partner interactions, to understand the connection from a centromeric nucleosome to a much larger microtubule...
November 3, 2016: Cell
https://www.readbyqxmd.com/read/27879374/molecular-determinants-of-ka1-domain-mediated-autoinhibition-and-phospholipid-activation-of-mark1-kinase
#5
Ryan P Emptage, Mark A Lemmon, Kathryn M Ferguson
Protein kinases are frequently regulated by intramolecular autoinhibitory interactions between protein modules that are reversed when these modules bind other 'activating' protein or membrane-bound targets.  One group of kinases, the M AP/ m icrotubule a ffinity- r egulating k inases (MARKs) contain a poorly understood regulatory module, the KA1 ( k inase a ssociated 1) domain, at their C-terminus.  KA1 domains from MARK1 and several related kinases from yeast to humans have been shown to bind membranes containing anionic phospholipids, and peptide ligands have also been reported...
November 22, 2016: Biochemical Journal
https://www.readbyqxmd.com/read/27820840/transcriptomic-analysis-of-responses-to-imbalanced-carbon-nitrogen-availabilities-in-rice-seedlings
#6
Aobo Huang, Yuying Sang, Wenfeng Sun, Ying Fu, Zhenbiao Yang
The internal C:N balance must be tightly controlled for the normal growth and development of plants. However, the underlying mechanisms, by which plants sense and balance the intracellular C:N status correspondingly to exogenous C:N availabilities remain elusive. In this study, we use comparative gene expression analysis to identify genes that are responsive to imbalanced C:N treatments in the aerial parts of rice seedlings. Transcripts of rice seedlings treated with four C:N availabilities (1:1, 1:60, 60:1 and 60:60) were compared and two groups of genes were classified: high C:low N responsive genes and low C:high N responsive genes...
2016: PloS One
https://www.readbyqxmd.com/read/27803165/galpha13-switch-region-2-relieves-talin-autoinhibition-to-activate-alphaiibbeta3-integrin
#7
James Schiemer, Andrew Bohm, Li Lin, Glenn Merrill-Skoloff, Robert Flaumenhaft, Jin-Sheng Huang, Guy C Le Breton, Athar H Chishti
Integrins function as bi-directional signaling transducers that regulate cell-cell and cell-matrix signals across the membrane. A key modulator of integrin activation is talin, a large cytoskeletal protein that exists in an autoinhibited state in quiescent cells. Talin is a large 235 kDa protein comprised of an N-terminal 45 kDa FERM domain, also known as the talin head domain (THD), and a series of helical bundles known as the rod domain. The talin head domain consists of 4 distinct lobes designated as F0-F3...
November 1, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27799534/sars-cov-3cl-protease-cleaves-its-c-terminal-autoprocessing-site-by-novel-subsite-cooperativity
#8
Tomonari Muramatsu, Chie Takemoto, Yong-Tae Kim, Hongfei Wang, Wataru Nishii, Takaho Terada, Mikako Shirouzu, Shigeyuki Yokoyama
The 3C-like protease (3CL(pro)) of severe acute respiratory syndrome coronavirus (SARS-CoV) cleaves 11 sites in the polyproteins, including its own N- and C-terminal autoprocessing sites, by recognizing P4-P1 and P1'. In this study, we determined the crystal structure of 3CL(pro) with the C-terminal prosequence and the catalytic-site C145A mutation, in which the enzyme binds the C-terminal prosequence of another molecule. Surprisingly, Phe at the P3' position [Phe(P3')] is snugly accommodated in the S3' pocket...
October 31, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27790061/lrrk2-inhibits-fak-activity-by-promoting-ferm-mediated-autoinhibition-of-fak-and-recruiting-the-tyrosine-phosphatase-shp-2
#9
Insup Choi, Ji-Won Byun, Sang Myun Park, Ilo Jou, Eun-Hye Joe
Mutation of leucine-rich repeat kinase 2 (LRRK2) causes an autosomal dominant and late-onset familial Parkinson's disease (PD). Recently, we reported that LRRK2 directly binds to and phosphorylates the threonine 474 (T474)-containing Thr-X-Arg(Lys) (TXR) motif of focal adhesion kinase (FAK), thereby inhibiting the phosphorylation of FAK at tyrosine (Y) 397 residue (pY397-FAK), which is a marker of its activation. Mechanistically, however, it remained unclear how T474-FAK phosphorylation suppressed FAK activation...
October 2016: Experimental Neurobiology
https://www.readbyqxmd.com/read/27768876/an-autoinhibited-dimeric-form-of-bax-regulates-the-bax-activation-pathway
#10
Thomas P Garner, Denis E Reyna, Amit Priyadarshi, Hui-Chen Chen, Sheng Li, Yang Wu, Yogesh Tengarai Ganesan, Vladimir N Malashkevich, Emily H Cheng, Evripidis Gavathiotis
No abstract text is available yet for this article.
October 20, 2016: Molecular Cell
https://www.readbyqxmd.com/read/27737911/drosophila-vinculin-is-more-harmful-when-hyperactive-than-absent-and-can-circumvent-integrin-to-form-adhesion-complexes
#11
Aidan P Maartens, Jutta Wellmann, Emma Wictome, Benjamin Klapholz, Hannah Green, Nicholas H Brown
Vinculin is a highly conserved protein involved in cell adhesion and mechanotransduction, and both gain and loss of its activity causes defective cell behaviour. Here, we examine how altering vinculin activity perturbs integrin function within the context of Drosophila development. Whereas loss of vinculin produced relatively minor phenotypes, gain of vinculin activity, through a loss of head-tail autoinhibition, caused lethality. The minimal domain capable of inducing lethality is the talin-binding D1 domain, and this appears to require talin-binding activity, as lethality was suppressed by competition with single vinculin-binding sites from talin...
December 1, 2016: Journal of Cell Science
https://www.readbyqxmd.com/read/27707755/constitutive-activation-of-dia1-diaph1-via-c-terminal-truncation-causes-human-sensorineural-hearing-loss
#12
Takehiko Ueyama, Yuzuru Ninoyu, Shin-Ya Nishio, Takushi Miyoshi, Hiroko Torii, Koji Nishimura, Kazuma Sugahara, Hideaki Sakata, Dean Thumkeo, Hirofumi Sakaguchi, Naoki Watanabe, Shin-Ichi Usami, Naoaki Saito, Shin-Ichiro Kitajiri
DIAPH1 encodes human DIA1, a formin protein that elongates unbranched actin. The c.3634+1G>T DIAPH1 mutation causes autosomal dominant nonsyndromic sensorineural hearing loss, DFNA1, characterized by progressive deafness starting in childhood. The mutation occurs near the C-terminus of the diaphanous autoregulatory domain (DAD) of DIA1, which interacts with its N-terminal diaphanous inhibitory domain (DID), and may engender constitutive activation of DIA1. However, the underlying pathogenesis that causes DFNA1 is unclear...
November 2, 2016: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/27706141/erratum-pore-forming-activity-and-structural-autoinhibition-of-the-gasdermin-family
#13
Jingjin Ding, Kun Wang, Wang Liu, Yang She, Qi Sun, Jianjin Shi, Hanzi Sun, Da-Cheng Wang, Feng Shao
No abstract text is available yet for this article.
December 1, 2016: Nature
https://www.readbyqxmd.com/read/27705767/binding-of-vinculin-to-lipid-membranes-in-its-inhibited-and-activated-states
#14
Mridula Dwivedi, Roland Winter
Phosphoinositols are an important class of phospholipids that are involved in a myriad of cellular processes, from cell signaling to motility and adhesion. Vinculin (Vn) is a major adaptor protein that regulates focal adhesions in conjunction with PIP2 in lipid membranes and other cytoskeletal components. The binding and unbinding transitions of Vn at the membrane interface are an important link to understanding the coordination of cell signaling and motility. Using different biophysical tools, including atomic force microscopy combined with confocal fluorescence microscopy and Fourier transform infrared spectroscopy, we studied the nanoscopic interactions of activated and autoinhibited states of Vn with lipid membranes...
October 4, 2016: Biophysical Journal
https://www.readbyqxmd.com/read/27704232/activating-glutamate-decarboxylase-activity-by-removing-the-autoinhibitory-domain-leads-to-hyper-%C3%AE-aminobutyric-acid-gaba-accumulation-in-tomato-fruit
#15
Mariko Takayama, Chiaki Matsukura, Tohru Ariizumi, Hiroshi Ezura
The C-terminal extension region of SlGAD3 is likely involved in autoinhibition, and removing this domain increases GABA levels in tomato fruits. γ-Aminobutyric acid (GABA) is a ubiquitous non-protein amino acid with several health-promoting benefits. In many plants including tomato, GABA is synthesized via decarboxylation of glutamate in a reaction catalyzed by glutamate decarboxylase (GAD), which generally contains a C-terminal autoinhibitory domain. We previously generated transgenic tomato plants in which tomato GAD3 (SlGAD3) was expressed using the 35S promoter/NOS terminator expression cassette (35S-SlGAD3-NOS), yielding a four- to fivefold increase in GABA levels in red-ripe fruits compared to the control...
October 4, 2016: Plant Cell Reports
https://www.readbyqxmd.com/read/27671644/sarm1-specific-motifs-in-the-tir-domain-enable-nad-loss-and-regulate-injury-induced-sarm1-activation
#16
Daniel W Summers, Daniel A Gibson, Aaron DiAntonio, Jeffrey Milbrandt
Axon injury in response to trauma or disease stimulates a self-destruction program that promotes the localized clearance of damaged axon segments. Sterile alpha and Toll/interleukin receptor (TIR) motif-containing protein 1 (SARM1) is an evolutionarily conserved executioner of this degeneration cascade, also known as Wallerian degeneration; however, the mechanism of SARM1-dependent neuronal destruction is still obscure. SARM1 possesses a TIR domain that is necessary for SARM1 activity. In other proteins, dimerized TIR domains serve as scaffolds for innate immune signaling...
October 11, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27666825/musk-kinase-activity-is-modulated-by-a-serine-phosphorylation-site-in-the-kinase-loop
#17
B Z Camurdanoglu, C Hrovat, G Dürnberger, M Madalinski, K Mechtler, R Herbst
The neuromuscular junction (NMJ) forms when a motor neuron contacts a muscle fibre. A reciprocal exchange of signals initiates a cascade of signalling events that result in pre- and postsynaptic differentiation. At the centre of these signalling events stands muscle specific kinase (MuSK). MuSK activation, kinase activity and subsequent downstream signalling are crucial for NMJ formation as well as maintenance. Therefore MuSK kinase activity is tightly regulated to ensure proper NMJ development. We have identified a novel serine phosphorylation site at position 751 in MuSK that is increasingly phosphorylated upon agrin stimulation...
September 26, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27632770/the-ataxia-related-g1107d-mutation-of-the-plasma-membrane-ca-2-atpase-isoform-3-affects-its-interplay-with-calmodulin-and-the-autoinhibition-process
#18
Tito Calì, Martina Frizzarin, Laura Luoni, Francesco Zonta, Sergio Pantano, Carlos Cruz, Maria Cristina Bonza, Ilenia Bertipaglia, Maria Ruzzene, Maria Ida De Michelis, Nunzio Damiano, Oriano Marin, Ginevra Zanni, Giuseppe Zanotti, Marisa Brini, Raffaele Lopreiato, Ernesto Carafoli
The plasma membrane Ca(2+) ATPases (PMCA pumps) have a long, cytosolic C-terminal regulatory region where a calmodulin-binding domain (CaM-BD) is located. Under basal conditions (low Ca(2+)), the C-terminal tail of the pump interacts with autoinhibitory sites proximal to the active center of the enzyme. In activating conditions (i.e., high Ca(2+)), Ca(2+)-bound CaM displaces the C-terminal tail from the autoinhibitory sites, restoring activity. We have recently identified a G1107D replacement within the CaM-BD of isoform 3 of the PMCA pump in a family affected by X-linked congenital cerebellar ataxia...
September 12, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27601635/coordinated-autoinhibition-of-f-bar-domain-membrane-binding-and-wasp-activation-by-nervous-wreck
#19
Tatiana B Stanishneva-Konovalova, Charlotte F Kelley, Tania L Eskin, Emily M Messelaar, Steven A Wasserman, Olga S Sokolova, Avital A Rodal
Membrane remodeling by Fes/Cip4 homology-Bin/Amphiphysin/Rvs167 (F-BAR) proteins is regulated by autoinhibitory interactions between their SRC homology 3 (SH3) and F-BAR domains. The structural basis of autoregulation, and whether it affects interactions of SH3 domains with other cellular ligands, remain unclear. Here we used single-particle electron microscopy to determine the structure of the F-BAR protein Nervous Wreck (Nwk) in both soluble and membrane-bound states. On membrane binding, Nwk SH3 domains do not completely dissociate from the F-BAR dimer, but instead shift from its concave surface to positions on either side of the dimer...
September 20, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27580057/regorafenib-stivarga-pharmacologically-targets-epithelial-mesenchymal-transition-in-colorectal-cancer
#20
Li-Ching Fan, Hao-Wei Teng, Chung-Wai Shiau, Wei-Tien Tai, Man-Hsin Hung, Shung-Haur Yang, Jeng-Kai Jiang, Kuen-Feng Chen
Epithelial-to-mesenchymal transition (EMT) is well-known to evoke cancer invasion/metastasis, leading to a high frequency of mortality in patients with metastatic colorectal cancer (mCRC). Protein tyrosine phosphatase (PTPase)-targeted therapy has been identified as a novel cancer therapeutic. Previously, we proved that sorafenib with anti-EMT potency prevents TGF-β1-induced EMT/invasion by directly activating SH2-domain-containing phosphatase 1 (SHP-1)-dependent p-STAT3Tyr705 suppression in hepatocellular carcinoma...
August 26, 2016: Oncotarget
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