keyword
MENU ▼
Read by QxMD icon Read
search

autoinhibition

keyword
https://www.readbyqxmd.com/read/29222176/ca2-releases-e-syt1-autoinhibition-to-couple-er-plasma-membrane-tethering-with-lipid-transport
#1
Xin Bian, Yasunori Saheki, Pietro De Camilli
The extended synaptotagmins (E-Syts) are endoplasmic reticulum (ER) proteins that bind the plasma membrane (PM) via C2 domains and transport lipids between them via SMP domains. E-Syt1 tethers and transports lipids in a Ca2+-dependent manner, but the role of Ca2+ in this regulation is unclear. Of the five C2 domains of E-Syt1, only C2A and C2C contain Ca2+-binding sites. Using liposome-based assays, we show that Ca2+ binding to C2C promotes E-Syt1-mediated membrane tethering by releasing an inhibition that prevents C2E from interacting with PI(4,5)P2-rich membranes, as previously suggested by studies in semi-permeabilized cells...
December 8, 2017: EMBO Journal
https://www.readbyqxmd.com/read/29220652/mechanistic-insights-into-autoinhibition-of-the-oncogenic-chromatin-remodeler-alc1
#2
Laura C Lehmann, Graeme Hewitt, Shintaro Aibara, Alexander Leitner, Emil Marklund, Sarah L Maslen, Varun Maturi, Yang Chen, David van der Spoel, J Mark Skehel, Aristidis Moustakas, Simon J Boulton, Sebastian Deindl
Human ALC1 is an oncogene-encoded chromatin-remodeling enzyme required for DNA repair that possesses a poly(ADP-ribose) (PAR)-binding macro domain. Its engagement with PARylated PARP1 activates ALC1 at sites of DNA damage, but the underlying mechanism remains unclear. Here, we establish a dual role for the macro domain in autoinhibition of ALC1 ATPase activity and coupling to nucleosome mobilization. In the absence of DNA damage, an inactive conformation of the ATPase is maintained by juxtaposition of the macro domain against predominantly the C-terminal ATPase lobe through conserved electrostatic interactions...
December 7, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29208644/filopodia-like-structure-formation-from-xenopus-egg-extracts
#3
Helen M Fox, Jennifer L Gallop
The actin cytoskeleton comprises many different architectures of filaments, including branched networks, parallel bundles and antiparallel fibers. A current challenge is to elucidate how the diverse array of actin regulators, which controls the growth, assembly and turnover of actin filaments, is used to orchestrate cytoskeletal organization and in turn cell shape and movement. Long observed to assemble at cell membranes, actin in Xenopus egg extracts recapitulates membrane-triggered assembly at specific lipid and membrane environments...
December 5, 2017: Cold Spring Harbor Protocols
https://www.readbyqxmd.com/read/29185419/activation-of-discs-large-by-apkc-aligns-the-mitotic-spindle-to-the-polarity-axis-during-asymmetric-cell-division
#4
Ognjen Golub, Brett Wee, Rhonda A Newman, Nicole M Paterson, Kenneth E Prehoda
Asymmetric division generates cellular diversity by producing daughter cells with different fates. In animals, the mitotic spindle aligns with Par complex polarized fate determinants, ensuring that fate determinant cortical domains are bisected by the cleavage furrow. Here, we investigate the mechanisms that couple spindle orientation to polarity during asymmetric cell division of Drosophila neuroblasts. We find that the tumor suppressor Discs large (Dlg) links the Par complex component atypical Protein Kinase C (aPKC) to the essential spindle orientation factor GukHolder (GukH)...
November 29, 2017: ELife
https://www.readbyqxmd.com/read/29161595/a-coincidence-detection-mechanism-controls-px-bar-domain-mediated-endocytic-membrane-remodeling-via-an-allosteric-structural-switch
#5
Wen-Ting Lo, Andreja Vujičić Žagar, Fabian Gerth, Martin Lehmann, Dymtro Puchkov, Oxana Krylova, Christian Freund, Leonardo Scapozza, Oscar Vadas, Volker Haucke
Clathrin-mediated endocytosis occurs by bending and remodeling of the membrane underneath the coat. Bin-amphiphysin-rvs (BAR) domain proteins are crucial for endocytic membrane remodeling, but how their activity is spatiotemporally controlled is largely unknown. We demonstrate that the membrane remodeling activity of sorting nexin 9 (SNX9), a late-acting endocytic PX-BAR domain protein required for constriction of U-shaped endocytic intermediates, is controlled by an allosteric structural switch involving coincident detection of the clathrin adaptor AP2 and phosphatidylinositol-3,4-bisphosphate (PI(3,4)P2) at endocytic sites...
November 20, 2017: Developmental Cell
https://www.readbyqxmd.com/read/29155350/the-pmca-pumps-in-genetically-determined-neuronal-pathologies
#6
REVIEW
Tito Calì, Marisa Brini, Ernesto Carafoli
Ca(2+) signals regulate most aspects of animal cell life. They are of particular importance to the nervous system, in which they regulate specific functions, from neuronal development to synaptic plasticity. The homeostasis of cell Ca(2+) must thus be very precisely regulated: in all cells Ca(2+) pumps transport it from the cytosol to the extracellular medium (the Plasma Membrane Ca(2+) ATPases, hereafter referred to as PMCA pumps) or to the lumen of intracellular organelles (the Sarco/Endoplasmatic Reticulum Ca(2+) ATPase and the Secretory Pathway Ca(2+) ATPase, hereafter referred to as SERCA and SPCA pumps, respectively)...
November 16, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/29149595/sterol-oxidation-mediates-stress-responsive-vms1-translocation-to-mitochondria
#7
Jason R Nielson, Eric K Fredrickson, T Cameron Waller, Olga Zurita Rendón, Heidi L Schubert, Zhenjian Lin, Christopher P Hill, Jared Rutter
Vms1 translocates to damaged mitochondria in response to stress, whereupon its binding partner, Cdc48, contributes to mitochondrial protein homeostasis. Mitochondrial targeting of Vms1 is mediated by its conserved mitochondrial targeting domain (MTD), which, in unstressed conditions, is inhibited by intramolecular binding to the Vms1 leucine-rich sequence (LRS). Here, we report a 2.7 Å crystal structure of Vms1 that reveals that the LRS lies in a hydrophobic groove in the autoinhibited MTD. We also demonstrate that the oxidized sterol, ergosterol peroxide, is necessary and sufficient for Vms1 localization to mitochondria, through binding the MTD in an interaction that is competitive with binding to the LRS...
November 16, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29142072/salt-bridges-gate-alpha-catenin-activation-at-intercellular-junctions
#8
Samantha Barrick, Jing Li, Xinyu Kong, Alokananda Ray, Emad Tajkhorshid, Deborah Leckband
Cadherin complexes transduce force fluctuations at junctions to activate signals that reinforce stressed intercellular contacts. α-Catenin is an identified force transducer within cadherin complexes that is autoinhibited under low tension. Increased force triggers a conformational change that exposes a cryptic site for the actin-binding protein vinculin. This study tested predictions that salt bridges within the force-sensing core modulate α-catenin activation. Studies with a fluorescence resonance energy transfer (FRET)-based α-catenin conformation sensor demonstrated that the salt-bridge mutations R551A and D503N each enhance α-catenin activation in live cells, but R551A has a greater impact...
November 15, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/29117520/phosphorylated-calmodulin-promotes-pi3k-activation-by-binding-to-the-sh2-domains
#9
Mingzhen Zhang, Hyunbum Jang, Vadim Gaponenko, Ruth Nussinov
How calmodulin (CaM) acts in KRAS-driven cancers is a vastly important question. CaM binds to and stimulates PI3Kα/Akt signaling, promoting cell growth and proliferation. Phosphorylation of CaM at Tyr(99) (pY99) enhances PI3Kα activation. PI3Kα is a lipid kinase. It phosphorylates PIP2 to produce PIP3, to which Akt binds. PI3Kα has two subunits: the regulatory p85 and the catalytic p110. Here, exploiting explicit-solvent MD simulations we unveil key interactions between phosphorylated CaM (pCaM) and the two SH2 domains in the p85 subunit, confirm experimental observations, and uncover PI3Kα's mechanism of activation...
November 7, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/29078407/intersectin-associates-with-synapsin-and-regulates-its-nanoscale-localization-and-function
#10
Fabian Gerth, Maria Jäpel, Arndt Pechstein, Gaga Kochlamazashvili, Martin Lehmann, Dmytro Puchkov, Franco Onofri, Fabio Benfenati, Alexander G Nikonenko, Tanja Maritzen, Christian Freund, Volker Haucke
Neurotransmission is mediated by the exocytic release of neurotransmitters from readily releasable synaptic vesicles (SVs) at the active zone. To sustain neurotransmission during periods of elevated activity, release-ready vesicles need to be replenished from the reserve pool of SVs. The SV-associated synapsins are crucial for maintaining this reserve pool and regulate the mobilization of reserve pool SVs. How replenishment of release-ready SVs from the reserve pool is regulated and which other factors cooperate with synapsins in this process is unknown...
November 7, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29058683/cooperative-mechanosensitivity-and-allostery-of-focal-adhesion-clusters
#11
Darryl C W Foo, Eugene Terentjev
We analyse a role of cooperative interaction between neighbouring adhesion-mechanosensor complexes by constructing an Ising-like Hamiltonian describing the free energy of cell adhesion on a substrate as a lattice of 3-state mechanosensing sites involving focal adhesion kinase (FAK). We use Monte Carlo stochastic algorithm to find equilibrium configurations of these mechanosensors in two representative geometries: on a 1D ring representing the rim of a cell on flat surface, and a 2D bounded surface representing the whole area of cell contact with flat surface...
October 23, 2017: Physical Biology
https://www.readbyqxmd.com/read/29045864/molecular-simulations-suggest-a-force-dependent-mechanism-of-vinculin-activation
#12
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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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 a crucial regulator of cytokinesis...
November 15, 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
#19
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...
October 3, 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
#20
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
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"