keyword
MENU ▼
Read by QxMD icon Read
search

autoinhibition

keyword
https://www.readbyqxmd.com/read/29045864/molecular-simulations-suggest-a-force-dependent-mechanism-of-vinculin-activation
#1
Li Sun, Jeffrey K Noel, Herbert Levine, José N Onuchic
Focal adhesions are dynamic constructs at the leading edge of migrating cells, linking them to the extracellular matrix and enabling force sensing and transmission. The lifecycle of a focal adhesion is a highly coordinated process involving spatial and temporal variations of protein composition, interaction, and cellular tension. The assembly of focal adhesions requires the recruitment and activation of vinculin. Vinculin is present in the cytoplasm in an autoinhibited conformation in which its tail is held pincerlike by its head domains, further stabilized by two high-affinity head-tail interfaces...
October 17, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/29029413/targeting-shp-1-stat3-signaling-a-promising-therapeutic-approach-for-the-treatment-of-cholangiocarcinoma
#2
Ming-Hung Hu, Li-Ju Chen, Yen-Lin Chen, Ming-Shen Tsai, Chung-Wai Shiau, Tzu-I Chao, Chun-Yu Liu, Jia-Horng Kao, Kuen-Feng Chen
Sorafenib is a multiple kinase inhibitor which targets Raf kinases, VEGFR, and PDGFR and is approved for the treatment of hepatocellular carcinoma (HCC). Previously, we found that p-STAT3 is a major target of SC-43, a sorafenib derivative. In this study, we report that SC-43-induced apoptosis in cholangiocarcinoma (CCA) via a novel mechanism. Three CCA cell lines (HuCCT-1, KKU-100 and CGCCA) were treated with SC-43 to determine their sensitivity to SC-43-induced cell death and apoptosis. We found that SC-43 activated SH2 domain-containing phosphatase 1 (SHP-1) activity, leading to p-STAT3 and downstream cyclin B1 and Cdc2 downregulation, which induced G2-M arrest and apoptotic cell death...
September 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/28978742/regulation-of-arf-activation-occurs-via-distinct-mechanisms-at-early-and-late-golgi-compartments
#3
Margaret A Gustafson, J Christopher Fromme
At the Golgi complex, the biosynthetic sorting center of the cell, the Arf GTPases are responsible for coordinating vesicle formation. The Arf-GEFs activate Arf GTPases and are therefore the key molecular decision-makers for trafficking from the Golgi.  In Saccharomyces cerevisiae, three conserved Arf-GEFs function at the Golgi: Sec7, Gea1, and Gea2.  Our group has described the regulation of Sec7, the trans-Golgi Arf-GEF, through autoinhibition, positive feedback, dimerization, and interactions with a suite of small GTPases...
October 4, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28972186/intramolecular-autoinhibition-of-checkpoint-kinase-1-is-mediated-by-conserved-basic-motifs-of-the-c-terminal-kinase-associated-1-domain
#4
Ryan P Emptage, Megan J Schoenberger, Kathryn M Ferguson, Ronen Marmorstein
Precise control of the cell cycle allows for timely repair of genetic material prior to replication. One factor intimately involved in this process is Chk1, a DNA damage repair inducing Ser/Thr protein kinase that contains an N-terminal kinase domain and a C-terminal regulatory region consisting of a ~100-residue linker followed by a putative kinase associated-1 (KA1) domain. We report the crystal structure of the human Chk1 KA1 domain, demonstrating striking structural homology with other sequentially diverse KA1 domains...
September 25, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28972136/the-mechanism-of-neural-precursor-cell-expressed-developmentally-down-regulated-4-2-nedd4-2-nedd4l-catalyzed-polyubiquitin-chain-assembly
#5
Dustin R Todaro, Allison C Augustus-Wallace, Jennifer M Klein, Arthur L Haas
The mechanism of Nedd4-2 has been quantitatively explored for the first time using biochemically-defined kinetic assays examining rates of (125)I-polyubiquitin chain assembly as a functional readout. We demonstrate that Nedd4-2 exhibits broad specificity for E2 paralogs of the Ubc4/5 clade to assemble Lys(63)-linked polyubiquitin chains. Full length Nedd4-2 catalyzes free (125)I-polyubiquitin chain assembly by hyperbolic Michaelis-Menten kinetics with respect to Ubc5B∼ubiquitin thioester concentration (KM = 44 ± 6 nM; kcat = 0...
September 28, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28952923/a-histidine-ph-sensor-regulates-activation-of-the-ras-specific-guanine-nucleotide-exchange-factor-rasgrp1
#6
Yvonne Vercoulen, Yasushi Kondo, Jeffrey S Iwig, Axel B Janssen, Katharine A White, Mojtaba Amini, Diane L Barber, John Kuriyan, Jeroen P Roose
RasGRPs are guanine nucleotide exchange factors that are specific for Ras or Rap, and are important regulators of cellular signaling. Aberrant expression or mutation of RasGRPs results in disease. An analysis of RasGRP1 SNP variants led to the conclusion that the charge of His 212 in RasGRP1 alters signaling activity and plasma membrane recruitment, indicating that His 212 is a pH sensor that alters the balance between the inactive and active forms of RasGRP1. To understand the structural basis for this effect we compared the structure of autoinhibited RasGRP1, determined previously, to those of active RasGRP4:H-Ras and RasGRP2:Rap1b complexes...
September 27, 2017: ELife
https://www.readbyqxmd.com/read/28931593/active-ran-regulates-anillin-function-during-cytokinesis
#7
Daniel Beaudet, Tara Akhshi, Julia Phillipp, Christopher Law, Alisa Piekny
Cytokinesis cleaves a cell into two daughters at the end of mitosis, and must be spatially coordinated with chromosome segregation to prevent aneuploidy. The dogma is that the mitotic spindle governs the assembly and constriction of an actomyosin ring. Here, we reveal a function for active Ran in spatially restricting the ring. Our model is that during anaphase, 'free' importins, whose gradient inversely correlates with active Ran and chromatin position, function as a molecular ruler for the recruitment and localization of anillin, a contractile protein and crucial regulator of cytokinesis...
September 20, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28928145/structure-insight-of-gsdmd-reveals-the-basis-of-gsdmd-autoinhibition-in-cell-pyroptosis
#8
Siyun Kuang, Jun Zheng, Hui Yang, Suhua Li, Shuyan Duan, Yanfang Shen, Chaoneng Ji, Jianhua Gan, Xue-Wei Xu, Jixi Li
Recent findings have revealed that the protein gasdermin D (GSDMD) plays key roles in cell pyroptosis. GSDMD binds lipids and forms pore structures to induce pyroptosis upon microbial infection and associated danger signals. However, detailed structural information for GSDMD remains unknown. Here, we report the crystal structure of the C-terminal domain of human GSDMD (GSDMD-C) at 2.64-Å resolution. The first loop on GSDMD-C inserts into the N-terminal domain (GSDMD-N), which helps stabilize the conformation of the full-length GSDMD...
September 19, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28916774/the-mechano-sensing-role-of-the-unique-sh3-insertion-in-plakin-domains-revealed-by-molecular-dynamics-simulations
#9
Csaba Daday, Katra Kolšek, Frauke Gräter
The plakin family of proteins, important actors in cross-linking force-bearing structures in the cell, contain a curious SH3 domain insertion in their chain of spectrin repeats (SRs). While SH3 domains are known to mediate protein-protein interactions, here, its canonical binding site is autoinhibited by the preceding SR. Under force, however, this SH3 domain could be released, and possibly launch a signaling cascade. We performed large-scale force-probe molecular dynamics simulations, across two orders of magnitude of loading rates, to test this hypothesis, on two prominent members of the plakin family: desmoplakin and plectin, obligate proteins at desmosomes and hemidesmosomes, respectively...
September 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28914978/model-informed-dose-optimization-of-dichloroacetate-for-the-treatment-of-congenital-lactic-acidosis-in-children
#10
Naveen Mangal, Margaret O James, Peter W Stacpoole, Stephan Schmidt
Dichloroacetate (DCA) is an investigational drug used to treat congenital lactic acidosis and other mitochondrial disorders. Response to DCA therapy in young children may be suboptimal following body weight-based dosing. This is because of autoinhibition of its metabolism, age-dependent changes in pharmacokinetics, and polymorphisms in glutathione transferase zeta 1 (GSTZ1), its primary metabolizing enzyme. Our objective was to predict optimal DCA doses for the treatment of congenital lactic acidosis in children...
September 15, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28883039/disease-associated-mutations-in-human-bicd2-hyperactivate-motility-of-dynein-dynactin
#11
Walter Huynh, Ronald D Vale
Bicaudal D2 (BICD2) joins dynein with dynactin into a ternary complex (termed DDB) capable of processive movement. Point mutations in the BICD2 gene have been identified in patients with a dominant form of spinal muscular atrophy, but how these mutations cause disease is unknown. To investigate this question, we have developed in vitro motility assays with purified DDB and BICD2's membrane vesicle partner, the GTPase Rab6a. Rab6a-GTP, either in solution or bound to artificial liposomes, released BICD2 from an autoinhibited state and promoted robust dynein-dynactin transport...
October 2, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28867612/achieving-a-graded-immune-response-btk-adopts-a-range-of-active-inactive-conformations-dictated-by-multiple-interdomain-contacts
#12
Raji E Joseph, Thomas E Wales, D Bruce Fulton, John R Engen, Amy H Andreotti
Capturing the functionally relevant forms of dynamic, multidomain proteins is extremely challenging. Bruton's tyrosine kinase (BTK), a kinase essential for B and mast cell function, has stubbornly resisted crystallization in its full-length form. Here, nuclear magnetic resonance and hydrogen-deuterium exchange mass spectrometry show that BTK adopts a closed conformation in dynamic equilibrium with open, active conformations. BTK lacks the phosphotyrosine regulatory tail of the SRC kinases, yet nevertheless achieves a phosphotyrosine-independent C-terminal latch...
October 3, 2017: Structure
https://www.readbyqxmd.com/read/28859110/junk-food-diet-induced-obesity-increases-d2-receptor-autoinhibition-in-the-ventral-tegmental-area-and-reduces-ethanol-drinking
#13
Jason B Cook, Linzy M Hendrickson, Grant M Garwood, Kelsey M Toungate, Christina V Nania, Hitoshi Morikawa
Similar to drugs of abuse, the hedonic value of food is mediated, at least in part, by the mesostriatal dopamine (DA) system. Prolonged intake of either high calorie diets or drugs of abuse both lead to a blunting of the DA system. Most studies have focused on DAergic alterations in the striatum, but little is known about the effects of high calorie diets on ventral tegmental area (VTA) DA neurons. Since high calorie diets produce addictive-like DAergic adaptations, it is possible these diets may increase addiction susceptibility...
2017: PloS One
https://www.readbyqxmd.com/read/28851890/effect-of-fluoride-treatment-on-gene-expression-in-tea-plant-camellia-sinensis
#14
Qing-Sheng Li, Xiao-Ming Lin, Ru-Ying Qiao, Xin-Qiang Zheng, Jian-Liang Lu, Jian-Hui Ye, Yue-Rong Liang
Tea plant is a typical fluorine (F) accumulator. F concentration in mature tea leaves is several hundred times higher than that in normal field crops. Long-term consumption of teas with high level F will increase the risks of dental and skeletal fluorosis. The mechanism of F accumulation in tea stands unclear. RNA-Seq and digital gene expression (DGE) techniques were used to investigate the effect of F on the differential expressions of transcriptome in tea plant. The results showed that F content in mature tea leaves was increased with increase in F concentration of cultural solution and duration of F treatment time...
August 29, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28842480/the-unique-c-terminus-of-the-calcineurin-isoform-cna%C3%AE-1-confers-non-canonical-regulation-of-enzyme-activity-by-ca-2-and-calmodulin
#15
Rachel Bond, Nina Ly, Martha S Cyert
Calcineurin, the conserved Ca(2+)/calmodulin-regulated phosphatase and target of immunosuppressants, plays important roles in the circulatory, nervous, and immune systems. Calcineurin activity strictly depends on Ca(2+) and Ca(2+)-bound calmodulin (Ca(2+)/CaM) to relieve autoinhibition of the catalytic subunit (CNA) by its C terminus. The C terminus contains two regulatory domains, the autoinhibitory domain (AID) and calmodulin-binding domain (CBD), which block the catalytic center and a conserved substrate-binding groove, respectively...
October 6, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28841137/autoinhibition-of-ankyrin-b-g-membrane-target-bindings-by-intrinsically-disordered-segments-from-the-tail-regions
#16
Keyu Chen, Jianchao Li, Chao Wang, Zhiyi Wei, Mingjie Zhang
Ankyrins together with their spectrin partners are the master organizers of micron-scale membrane domains in diverse tissues. The 24 ankyrin (ANK) repeats of ankyrins bind to numerous membrane proteins, linking them to spectrin-based cytoskeletons at specific membrane microdomains. The accessibility of the target binding groove of ANK repeats must be regulated to achieve spatially defined functions of ankyrins/target complexes in different tissues, though little is known in this regard. Here we systemically investigated the autoinhibition mechanism of ankyrin-B/G by combined biochemical, biophysical and structural biology approaches...
August 25, 2017: ELife
https://www.readbyqxmd.com/read/28838668/copper-and-zinc-promoted-interdomain-structure-in-the-prion-protein-a-mechanism-for-autoinhibition-of-the-neurotoxic-n-terminus
#17
Eric G B Evans, Glenn L Millhauser
The function of the cellular prion protein (PrP(C)), while still poorly understood, is increasingly linked to its ability to bind physiological metal ions at the cell surface. PrP(C) binds divalent forms of both copper and zinc through its unstructured N-terminal domain, modulating interactions between PrP(C) and various receptors at the cell surface and ultimately tuning downstream cellular processes. In this chapter, we briefly discuss the molecular features of copper and zinc uptake by PrP(C) and summarize evidence implicating these metal ions in PrP-mediated physiology...
2017: Progress in Molecular Biology and Translational Science
https://www.readbyqxmd.com/read/28813247/switch-like-arp2-3-activation-upon-wasp-and-wip-recruitment-to-an-apparent-threshold-level-by-multivalent-linker-proteins-in-vivo
#18
Yidi Sun, Nicole T Leong, Tommy Jiang, Astou Tangara, Xavier Darzacq, David G Drubin
Actin-related protein 2/3 (Arp2/3) complex activation by nucleation promoting factors (NPFs) such as WASP, plays an important role in many actin-mediated cellular processes. In yeast, Arp2/3-mediated actin filament assembly drives endocytic membrane invagination and vesicle scission. Here we used genetics and quantitative live-cell imaging to probe the mechanisms that concentrate NPFs at endocytic sites, and to investigate how NPFs regulate actin assembly onset. Our results demonstrate that SH3 (Src homology 3) domain-PRM (proline-rich motif) interactions involving multivalent linker proteins play central roles in concentrating NPFs at endocytic sites...
August 16, 2017: ELife
https://www.readbyqxmd.com/read/28772159/structure-based-design-of-competitive-ligands-to-target-spon2-in-gastric-cancer-an-integration-of-molecular-modeling-and-in-vitro-assay
#19
Zhenglei Xu, Zhichao Yu, Shumei Nai, Ruiyue Shi, Qinhong Tang, Haiyang Zhang, Lijuan Ye, Lisheng Wang, Yincai Hong
Spon2 is a proto-oncogene matrix protein that plays an essential role in the tumorigenesis and metastasis of gastric cancer. The protein has recently been found to function as a guanine nucleotide exchange factor through the activation of RhoGTPase. Here, computational modeling and bioinformatics analysis were employed to investigate the molecular mechanism and biological implication underlying Spon2 autoinhibition. It is revealed that the binding of PxxP motif to SH domain can stabilize the intramolecular interaction between the N-terminal helix and DH domain of Spon2, thus shifting the protein into an autoinhibitory state...
October 2017: Bioorganic Chemistry
https://www.readbyqxmd.com/read/28772122/a-c1-c2-module-in-munc13-inhibits-calcium-dependent-neurotransmitter-release
#20
Francesco Michelassi, Haowen Liu, Zhitao Hu, Jeremy S Dittman
Almost all known forms of fast chemical synaptic transmission require the synaptic hub protein Munc13. This essential protein has also been implicated in mediating several forms of use-dependent plasticity, but the mechanisms by which it controls vesicle fusion and plasticity are not well understood. Using the C. elegans Munc13 ortholog UNC-13, we show that deletion of the C2B domain, the most highly conserved domain of Munc13, enhances calcium-dependent exocytosis downstream of vesicle priming, revealing a novel autoinhibitory role for the C2B...
August 2, 2017: Neuron
keyword
keyword
98505
1
2
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read
×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"