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https://www.readbyqxmd.com/read/28069708/ubiquitylation-dependent-oligomerization-regulates-activity-of-nedd4-ligases
#1
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
#2
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
#3
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...
December 22, 2016: 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
#4
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
#5
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-nanodisc-reconstituted-vacuolar-atpase-proton-channel-definition-of-the-interaction-of-rotor-and-stator-and-implications-for-enzyme-regulation-by-reversible-dissociation
#6
Nicholas J Stam, Stephan Wilkens
Eukaryotic vacuolar H+-ATPase (V-ATPase) is a multi-subunit 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 electron microscopy (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...
December 13, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27899597/thermotoga-maritima-nusg-domain-interaction-mediates-autoinhibition-and-thermostability
#7
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
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
#8
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-verprolin-homology-cofilin-acidic-vca-domain
#9
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 mediates 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 requires N-WASP for this process, the molecular details of this interaction and the mechanism of N-WASP activation remain poorly understood...
January 6, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27881300/structure-of-the-mind-complex-defines-a-regulatory-focus-for-yeast-kinetochore-assembly
#10
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
#11
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
#12
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/g%C3%AE-13-switch-region-2-relieves-talin-autoinhibition-to-activate-%C3%AE-iib%C3%AE-3-integrin
#13
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 composed of an N-terminal 45-kDa FERM (4.1, ezrin-, radixin-, and moesin-related protein) domain, also known as the talin head domain, and a series of helical bundles known as the rod domain. The talin head domain consists of four distinct lobes designated as F0-F3...
December 23, 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
#14
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...
November 15, 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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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