keyword
MENU ▼
Read by QxMD icon Read
search

autoinhibition

keyword
https://www.readbyqxmd.com/read/29419884/balancing-tonic-and-phasic-inhibition-in-hypothalamic-corticotropin-releasing-hormone-neurons
#1
Phillip L W Colmers, Jaideep S Bains
Corticotropin releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN) are integratory hubs that regulate the endocrine response to stress. GABA inputs provide a basal inhibitory tone that constrains this system and circulating glucocorticoids (CORT) are important feedback controllers of CRH output. Surprisingly little is known about the direct effects of CORT on GABA synapses in PVN. Here we used whole-cell patch clamp recordings from CRH neurons in mouse hypothalamic brain slices to examine the effects of CORT on synaptic and extrasynaptic GABA signalling...
February 8, 2018: Journal of Physiology
https://www.readbyqxmd.com/read/29408528/structural-conservation-of-the-autoinhibitory-domain-in-sun-proteins
#2
Yang Xu, Wei Li, Huimin Ke, Wei Feng
LINC complexes span across the nuclear envelope and are assembled by SUN and KASH proteins. SUN1 and SUN2 are the two most abundant SUN proteins in mammals. In SUN2, the predicted coiled-coil domain preceding the SUN domain forms a three-helix bundle that constitutes an autoinhibitory domain (AID) to lock down the SUN domain. Here, we found that SUN1 also contains an AID preceding the SUN domain and solved the structure of the AID-SUN tandem of SUN1. SUN1 AID also adopts a three-helix bundle conformation that interacts with the SUN domain and keeps it in an autoinhibited state...
February 3, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29396291/novel-structural-mechanism-of-allosteric-regulation-of-aspartic-peptidases-via-an-evolutionarily-conserved-exosite
#3
Iva Hánová, Jiří Brynda, Radka Houštecká, Nawsad Alam, Daniel Sojka, Petr Kopáček, Lucie Marešová, Jiří Vondrášek, Martin Horn, Ora Schueler-Furman, Michael Mareš
Pepsin-family aspartic peptidases are biosynthesized as inactive zymogens in which the propeptide blocks the active site until its proteolytic removal upon enzyme activation. Here, we describe a novel dual regulatory function for the propeptide using a set of crystal structures of the parasite cathepsin D IrCD1. In the IrCD1 zymogen, intramolecular autoinhibition by the intact propeptide is mediated by an evolutionarily conserved exosite on the enzyme core. After activation, the mature enzyme employs the same exosite to rebind a small fragment derived from the cleaved propeptide...
January 26, 2018: Cell Chemical Biology
https://www.readbyqxmd.com/read/29395785/structural-architecture-of-the-nucleosome-remodeler-iswi-determined-from-cross-linking-mass-spectrometry-saxs-and-modeling
#4
Nadine Harrer, Christina E M Schindler, Linda K Bruetzel, Ignasi Forné, Johanna Ludwigsen, Axel Imhof, Martin Zacharias, Jan Lipfert, Felix Mueller-Planitz
Chromatin remodeling factors assume critical roles by regulating access to nucleosomal DNA. To determine the architecture of the Drosophila ISWI remodeling enzyme, we developed an integrative structural approach that combines protein cross-linking, mass spectrometry, small-angle X-ray scattering, and computational modeling. The resulting structural model shows the ATPase module in a resting state with both ATPase lobes twisted against each other, providing support for a conformation that was recently trapped by crystallography...
February 6, 2018: Structure
https://www.readbyqxmd.com/read/29395043/calcium-calmodulin-dependent-protein-kinase-ii-and-eukaryotic-elongation-factor-2-kinase-pathways-mediate-the-antidepressant-action-of-ketamine
#5
Chinnakkaruppan Adaikkan, Elham Taha, Iliana Barrera, Orit David, Kobi Rosenblum
BACKGROUND: Ketamine is an N-methyl-D-aspartate receptor antagonist, which on administration produces fast-acting antidepressant responses in patients with major depressive disorder. Yet, the mechanism underlying the antidepressant action of ketamine remains unclear. METHODS: To unravel the mechanism of action of ketamine, we treated wild-type C57BL/6 mice with calcium/calmodulin-dependent protein kinase II (CaMKII) specific inhibitor tatCN21 peptide. We also used eukaryotic elongation factor 2 kinase (eEF2K) (also known as CaMKIII) knockout mice...
December 5, 2017: Biological Psychiatry
https://www.readbyqxmd.com/read/29349444/non-invasive-force-measurement-reveals-the-number-of-active-kinesins-on-a-synaptic-vesicle-precursor-in-axonal-transport-regulated-by-arl-8
#6
Kumiko Hayashi, Shin Hasegawa, Takashi Sagawa, Sohei Tasaki, Shinsuke Niwa
Kinesin superfamily protein UNC-104, a member of the kinesin-3 family, transports synaptic vesicle precursors (SVPs). In this study, the number of active UNC-104 molecules hauling a single SVP in axons in the worm Caenorhabditis elegans was counted by applying a newly developed non-invasive force measurement technique. The distribution of the force acting on a SVP transported by UNC-104 was spread out over several clusters, implying the presence of several force-producing units (FPUs). We then compared the number of FPUs in the wild-type worms with that in arl-8 gene-deletion mutant worms...
January 19, 2018: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/29343782/protein-phosphatase-5-regulates-titin-phosphorylation-and-function-at-a-sarcomere-associated-mechanosensor-complex-in-cardiomyocytes
#7
Judith Krysiak, Andreas Unger, Lisa Beckendorf, Nazha Hamdani, Marion von Frieling-Salewsky, Margaret M Redfield, Cris G Dos Remedios, Farah Sheikh, Ulrich Gergs, Peter Boknik, Wolfgang A Linke
Serine/threonine protein phosphatase 5 (PP5) is ubiquitously expressed in eukaryotic cells; however, its function in cardiomyocytes is unknown. Under basal conditions, PP5 is autoinhibited, but enzymatic activity rises upon binding of specific factors, such as the chaperone Hsp90. Here we show that PP5 binds and dephosphorylates the elastic N2B-unique sequence (N2Bus) of titin in cardiomyocytes. Using various binding and phosphorylation tests, cell-culture manipulation, and transgenic mouse hearts, we demonstrate that PP5 associates with N2Bus in vitro and in sarcomeres and is antagonistic to several protein kinases, which phosphorylate N2Bus and lower titin-based passive tension...
January 17, 2018: Nature Communications
https://www.readbyqxmd.com/read/29305430/revisiting-paradigms-of-ca2-signaling-protein-kinase-regulation-in-plants
#8
REVIEW
Kyle W Bender, Raymond E Zielinski, Steven C Huber
Calcium (Ca2+) serves as a universal second messenger in eukaryotic signal transduction. Understanding the Ca2+ activation kinetics of Ca2+ sensors is critical to understanding the cellular signaling mechanisms involved. In this review, we discuss the regulatory properties of two sensor classes: the Ca2+-dependent protein kinases (CPKs/CDPKs) and the calcineurin B-like (CBL) proteins that control the activity of CBL-interacting protein kinases (CIPKs) and identify emerging topics and some foundational points that are not well established experimentally...
January 5, 2018: Biochemical Journal
https://www.readbyqxmd.com/read/29288204/novel-tcr-mediated-mechanisms-of-notch-activation-and-signaling
#9
Martin Peter Steinbuck, Ksenia Arakcheeva, Susan Winandy
The Notch receptor is an evolutionarily highly conserved transmembrane protein that is essential to a wide spectrum of cellular systems. Notch signaling is especially important to T cell development, and its deregulation leads to leukemia. Although not well characterized, it continues to play an integral role in peripheral T cells, in which a unique mode of Notch activation can occur. In contrast to canonical Notch activation initiated by adjacent ligand-expressing cells, TCR stimulation is sufficient to induce Notch signaling...
December 29, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29276036/structural-dynamics-control-allosteric-activation-of-cytohesin-family-arf-gtpase-exchange-factors
#10
Andrew W Malaby, Sanchaita Das, Srinivas Chakravarthy, Thomas C Irving, Osman Bilsel, David G Lambright
Membrane dynamic processes including vesicle biogenesis depend on Arf guanosine triphosphatase (GTPase) activation by guanine nucleotide exchange factors (GEFs) containing a catalytic Sec7 domain and a membrane-targeting module such as a pleckstrin homology (PH) domain. The catalytic output of cytohesin family Arf GEFs is controlled by autoinhibitory interactions that impede accessibility of the exchange site in the Sec7 domain. These restraints can be relieved through activator Arf-GTP binding to an allosteric site comprising the PH domain and proximal autoinhibitory elements (Sec7-PH linker and C-terminal helix)...
December 16, 2017: Structure
https://www.readbyqxmd.com/read/29237558/atg7-activates-an-autophagy-essential-ubiquitin-like-protein-atg8-through-multi-step-recognition
#11
Masaya Yamaguchi, Kenji Satoo, Hironori Suzuki, Yuko Fujioka, Yoshinori Ohsumi, Fuyuhiko Inagaki, Nobuo N Noda
Atg8 is a unique ubiquitin-like protein that is covalently conjugated with a phosphatidylethanolamine through reactions similar to ubiquitination and plays essential roles in autophagy. Atg7 is the E1 enzyme for Atg8, and it activates the C-terminal Gly116 of Atg8 using ATP. Here, we report the crystal structure of Atg8 bound to the C-terminal domain of Atg7 in an unprecedented mode. Atg8 neither contacts with the central β-sheet nor binds to the catalytic site of Atg7, both of which were observed in previously reported Atg7-Atg8 structures...
December 10, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/29234112/a-switch-in-nucleotide-affinity-governs-activation-of-the-src-and-tec-family-kinases
#12
Freia von Raußendorf, Anita de Ruiter, Thomas A Leonard
The Tec kinases, closely related to Src family kinases, are essential for lymphocyte function in the adaptive immune system. Whilst the Src and Abl kinases are regulated by tail phosphorylation and N-terminal myristoylation respectively, the Tec kinases are notable for the absence of either regulatory element. We have found that the inactive conformations of the Tec kinase Itk and Src preferentially bind ADP over ATP, stabilising both proteins. We demonstrate that Itk adopts the same conformation as Src and that the autoinhibited conformation of Src is independent of its C-terminal tail...
December 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29229862/a-small-molecule-activator-of-kinesin-1-drives-remodeling-of-the-microtubule-network
#13
Thomas S Randall, Yan Y Yip, Daynea J Wallock-Richards, Karin Pfisterer, Anneri Sanger, Weronika Ficek, Roberto A Steiner, Andrew J Beavil, Maddy Parsons, Mark P Dodding
The microtubule motor kinesin-1 interacts via its cargo-binding domain with both microtubules and organelles, and hence plays an important role in controlling organelle transport and microtubule dynamics. In the absence of cargo, kinesin-1 is found in an autoinhibited conformation. The molecular basis of how cargo engagement affects the balance between kinesin-1's active and inactive conformations and roles in microtubule dynamics and organelle transport is not well understood. Here we describe the discovery of kinesore, a small molecule that in vitro inhibits kinesin-1 interactions with short linear peptide motifs found in organelle-specific cargo adaptors, yet activates kinesin-1's function of controlling microtubule dynamics in cells, demonstrating that these functions are mechanistically coupled...
December 11, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29224781/structural-basis-for-regulated-proteolysis-by-the-%C3%AE-secretase-adam10
#14
Tom C M Seegar, Lauren B Killingsworth, Nayanendu Saha, Peter A Meyer, Dhabaleswar Patra, Brandon Zimmerman, Peter W Janes, Eric Rubinstein, Dimitar B Nikolov, Georgios Skiniotis, Andrew C Kruse, Stephen C Blacklow
Cleavage of membrane-anchored proteins by ADAM (a disintegrin and metalloproteinase) endopeptidases plays a key role in a wide variety of biological signal transduction and protein turnover processes. Among ADAM family members, ADAM10 stands out as particularly important because it is both responsible for regulated proteolysis of Notch receptors and catalyzes the non-amyloidogenic α-secretase cleavage of the Alzheimer's precursor protein (APP). We present here the X-ray crystal structure of the ADAM10 ectodomain, which, together with biochemical and cellular studies, reveals how access to the enzyme active site is regulated...
December 14, 2017: Cell
https://www.readbyqxmd.com/read/29222176/ca2-releases-e-syt1-autoinhibition-to-couple-er-plasma-membrane-tethering-with-lipid-transport
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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"