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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
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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...
February 3, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28124908/structural-insights-how-pip2-imposes-preferred-binding-orientations-of-fak-at-lipid-membranes
#12
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
https://www.readbyqxmd.com/read/28115697/mechanism-of-catalysis-e2-recognition-and-autoinhibition-for-the-ipah-family-of-bacterial-e3-ubiquitin-ligases
#13
Alexander F A Keszei, Frank Sicheri
IpaH enzymes are secreted bacterial effectors that function within host cells as E3 ubiquitin (Ub) ligases. Catalytic activity is imparted by a conserved novel E3 ligase (NEL) domain that is unique to Gram-negative pathogens and whose activity is repressed by a flanking substrate-binding leucine-rich repeat (LRR) domain when substrate is absent. How the NEL domain catalyzes the conjugation of Ub onto substrates, recognizes host E2s, and maintains its autoinhibited state remain poorly understood. Here we used mutagenesis and enzyme kinetic analyses to address these gaps in knowledge...
February 7, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28069708/ubiquitylation-dependent-oligomerization-regulates-activity-of-nedd4-ligases
#14
Ilan Attali, William Sam Tobelaim, Avinash Persaud, Khatereh Motamedchaboki, Kobi J Simpson-Lavy, Bayan Mashahreh, Olga Levin-Kravets, Tal Keren-Kaplan, Inbar Pilzer, Martin Kupiec, Reuven Wiener, Dieter A Wolf, Daniela Rotin, Gali Prag
Ubiquitylation controls protein function and degradation. Therefore, ubiquitin ligases need to be tightly controlled. We discovered an evolutionarily conserved allosteric restraint mechanism for Nedd4 ligases and demonstrated its function with diverse substrates: the yeast soluble proteins Rpn10 and Rvs167, and the human receptor tyrosine kinase FGFR1 and cardiac IKS potassium channel. We found that a potential trimerization interface is structurally blocked by the HECT domain α1-helix, which further undergoes ubiquitylation on a conserved lysine residue...
January 9, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28053243/descending-antinociception-induced-by-secondary-somatosensory-cortex-stimulation-in-experimental-neuropathy-role-of-the-medullospinal-serotonergic-pathway
#15
Boriss Sagalajev, Hanna Viisanen, Hong Wei, Antti Pertovaara
Stimulation of the secondary somatosensory cortex (S2) has attenuated pain in humans and inflammatory nociception in animals. Here we studied S2 stimulation-induced antinociception and its underlying mechanisms in an experimental animal model of neuropathy induced by spinal nerve ligation (SNL). Effect of S2 stimulation on heat-evoked limb withdrawal latency was assessed in lightly anesthetized rats that were divided into three groups based on prior surgery and monofilament testing before induction of anesthesia: i) Sham operated group, ii-iii) (mechanically) hypersensitive and non-hypersensitive SNL groups...
January 4, 2017: Journal of Neurophysiology
https://www.readbyqxmd.com/read/28007983/structure-of-phosphorylated-ubl-domain-and-insights-into-pink1-orchestrated-parkin-activation
#16
Jacob D Aguirre, Karen M Dunkerley, Pascal Mercier, Gary S Shaw
Mutations in PARK2 and PARK6 genes are responsible for the majority of hereditary Parkinson's disease cases. These genes encode the E3 ubiquitin ligase parkin and the protein kinase PTEN-induced kinase 1 (PINK1), respectively. Together, parkin and PINK1 regulate the mitophagy pathway, which recycles damaged mitochondria following oxidative stress. Native parkin is inactive and exists in an autoinhibited state mediated by its ubiquitin-like (UBL) domain. PINK1 phosphorylation of serine 65 in parkin's UBL and serine 65 of ubiquitin fully activate ubiquitin ligase activity; however, a structural rationale for these observations is not clear...
January 10, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28001127/cryo-em-structures-of-the-autoinhibited-e-coli-atp-synthase-in-three-rotational-states
#17
Meghna Sobti, Callum Smits, Andrew Sw Wong, Robert Ishmukhametov, Daniela Stock, Sara Sandin, Alastair G Stewart
A molecular model that provides a framework for interpreting the wealth of functional information obtained on the E. coli F-ATP synthase has been generated using cryo-electron microscopy. Three different states that relate to rotation of the enzyme were observed, with the central stalk's ε subunit in an extended autoinhibitory conformation in all three states. The Fo motor comprises of seven transmembrane helices and a decameric c-ring and invaginations on either side of the membrane indicate the entry and exit channels for protons...
December 21, 2016: ELife
https://www.readbyqxmd.com/read/27977001/relief-of-autoinhibition-by-conformational-switch-explains-enzyme-activation-by-a-catalytically-dead-paralog
#18
Oleg A Volkov, Lisa Kinch, Carson Ariagno, Xiaoyi Deng, Shihua Zhong, Nick Grishin, Diana R Tomchick, Zhe Chen, Margaret A Phillips
Catalytically inactive enzyme paralogs occur in many genomes. Some regulate their active counterparts but the structural principles of this regulation remain largely unknown. We report X-ray structures of Trypanosoma brucei S-adenosylmethionine decarboxylase alone and in functional complex with its catalytically dead paralogous partner, prozyme. We show monomeric TbAdoMetDC is inactive because of autoinhibition by its N-terminal sequence. Heterodimerization with prozyme displaces this sequence from the active site through a complex mechanism involving a cis-to-trans proline isomerization, reorganization of a β-sheet, and insertion of the N-terminal α-helix into the heterodimer interface, leading to enzyme activation...
December 15, 2016: ELife
https://www.readbyqxmd.com/read/27965356/structure-of-the-lipid-nanodisc-reconstituted-vacuolar-atpase-proton-channel-definition-of-the-interaction-of-rotor-and-stator-and-implications-for-enzyme-regulation-by-reversible-dissociation
#19
Nicholas J Stam, Stephan Wilkens
Eukaryotic vacuolar H(+)-ATPase (V-ATPase) is a multisubunit enzyme complex that acidifies subcellular organelles and the extracellular space. V-ATPase consists of soluble V1-ATPase and membrane-integral Vo proton channel sectors. To investigate the mechanism of V-ATPase regulation by reversible disassembly, we recently determined a cryo-EM reconstruction of yeast Vo The structure indicated that, when V1 is released from Vo, the N-terminal cytoplasmic domain of subunit a (aNT) changes conformation to bind rotor subunit d However, insufficient resolution precluded a precise definition of the aNT-d interface...
February 3, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27899597/thermotoga-maritima-nusg-domain-interaction-mediates-autoinhibition-and-thermostability
#20
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...
January 9, 2017: Nucleic Acids Research
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