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https://www.readbyqxmd.com/read/28522792/transgenic-autoinhibition-of-p21-activated-kinase-exacerbates-synaptic-impairments-and-fronto-dependent-behavioral-deficits-in-an-animal-model-of-alzheimer-s-disease
#1
Cyril Bories, Dany Arsenault, Myriam Lemire, Cyntia Tremblay, Yves De Koninck, Frédéric Calon
Defects in p21-activated kinase (PAK) lead to dendritic spine abnormalities and are sufficient to cause cognition impairment. The decrease in PAK in the brain of Alzheimer's disease (AD) patients is suspected to underlie synaptic and dendritic disturbances associated with its clinical expression, particularly with symptoms related to frontal cortex dysfunction. To investigate the role of PAK combined with Aβ and tau pathologies (3xTg-AD mice) in the frontal cortex, we generated a transgenic model of AD with a deficit in PAK activity (3xTg-AD-dnPAK mice)...
May 16, 2017: Aging
https://www.readbyqxmd.com/read/28500026/the-hect-e3-ubiquitin-ligase-wwp2-is-autoinhibited-by-a-peptide-linker
#2
(no author information available yet)
Peptide linkers that tether WWP2 WW domains lock the HECT domain in an inactive conformation.
May 12, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28486782/role-of-n-glycosylation-in-egfr-ectodomain-ligand-binding
#3
Maryam Azimzadeh Irani, Srinivasaraghavan Kannan, Chandra Verma
The Epidermal Growth Factor Receptor (EGFR) is a tyrosine kinase protein, overexpressed in several cancers. The extracellular domain of EGFR is known to be heavily glycosylated. Growth factor (mostly Epidermal Growth Factor or EGF) binding activates EGFR. This occurs by inducing the transition from the autoinhibited tethered conformation to an extended conformation of the monomeric form of EGFR and by stabilizing the flexible pre-formed dimer. Activated EGFR adopts a back-to-back dimeric conformation after binding of another homologous receptor to its extracellular domain as the dimeric partner...
May 9, 2017: Proteins
https://www.readbyqxmd.com/read/28477408/autoinhibition-of-munc18-1-modulates-synaptobrevin-binding-and-helps-to-enable-munc13-dependent-regulation-of-membrane-fusion
#4
Ewa Sitarska, Junjie Xu, Seungmee Park, Xiaoxia Liu, Bradley Quade, Karolina Stepien, Kyoko Sugita, Chad A Brautigam, Shuzo Sugita, Josep Rizo
Munc18-1 orchestrates SNARE complex assembly together with Munc13-1 to mediate neurotransmitter release. Munc18-1 binds to synaptobrevin, but the relevance of this interaction and its relation to Munc13 function are unclear. NMR experiments now show that Munc18-1 binds specifically and non-specifically to synaptobrevin. Specific binding is inhibited by a L348R mutation in Munc18-1 and enhanced by a D326K mutation designed to disrupt the 'furled conformation' of a Munc18-1 loop. Correspondingly, the activity of Munc18-1 in reconstitution assays that require Munc18-1 and Munc13-1 for membrane fusion is stimulated by the D326K mutation and inhibited by the L348R mutation...
May 6, 2017: ELife
https://www.readbyqxmd.com/read/28475870/a-tunable-brake-for-hect-ubiquitin-ligases
#5
Zan Chen, Hanjie Jiang, Wei Xu, Xiaoguang Li, Daniel R Dempsey, Xiangbin Zhang, Peter Devreotes, Cynthia Wolberger, L Mario Amzel, Sandra B Gabelli, Philip A Cole
The HECT E3 ligases ubiquitinate numerous transcription factors and signaling molecules, and their activity must be tightly controlled to prevent cancer, immune disorders, and other diseases. In this study, we have found unexpectedly that peptide linkers tethering WW domains in several HECT family members are key regulatory elements of their catalytic activities. Biochemical, structural, and cellular analyses have revealed that the linkers can lock the HECT domain in an inactive conformation and block the proposed allosteric ubiquitin binding site...
May 4, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28459430/chemotherapy-drugs-induce-pyroptosis-through-caspase-3-cleavage-of-a-gasdermin
#6
Yupeng Wang, Wenqing Gao, Xuyan Shi, Jingjin Ding, Wang Liu, Huabin He, Kun Wang, Feng Shao
Pyroptosis, activated by the canonical caspase-1 inflammasomes or caspase-4/5/11 by cytosolic LPS, is critical for immunity(1,2,3). The caspases cleave Gasdermin D (GSDMD) in the middle linker to release autoinhibition on its Gasdermin-N domain that executes pyroptosis via the pore-forming activity(4,5,6,7,8,9). GSDMD belongs to a Gasdermin family sharing the pore-forming domain(4,6,10). The function and mechanism of activation for other Gasdermins are unknown. Here we show that GSDME, originally identified as DFNA5 (Deafness, Autosomal Dominant 5)(11), could switch TNFα or chemotherapy drugs-induced and caspase-3-mediated apoptosis to pyroptosis...
May 1, 2017: Nature
https://www.readbyqxmd.com/read/28452363/mechanism-of-sos-pr-domain-autoinhibition-revealed-by-single-molecule-assays-on-native-protein-from-lysate
#7
Young Kwang Lee, Shalini T Low-Nam, Jean K Chung, Scott D Hansen, Hiu Yue Monatrice Lam, Steven Alvarez, Jay T Groves
The guanine nucleotide exchange factor (GEF) Son of Sevenless (SOS) plays a critical role in signal transduction by activating Ras. Here we introduce a single-molecule assay in which individual SOS molecules are captured from raw cell lysate using Ras-functionalized supported membrane microarrays. This enables characterization of the full-length SOS protein, which has not previously been studied in reconstitution due to difficulties in purification. Our measurements on the full-length protein reveal a distinct role of the C-terminal proline-rich (PR) domain to obstruct the engagement of allosteric Ras independently of the well-known N-terminal domain autoinhibition...
April 28, 2017: Nature Communications
https://www.readbyqxmd.com/read/28438902/crucial-role-of-rock2-mediated-phosphorylation-and-upregulation-of-fhod3-in-the-pathogenesis-of-angiotensin-ii-induced-cardiac-hypertrophy
#8
Qing Zhou, Si-Si Wei, Hong Wang, Qian Wang, Wei Li, Gang Li, Jian-Wen Hou, Xiao-Meng Chen, Jie Chen, Wei-Ping Xu, Yi-Gang Li, Yue-Peng Wang
Cardiac hypertrophy is characterized by increased myofibrillogenesis. Angiotensin II (Ang-II) is an essential mediator of the pressure overload-induced cardiac hypertrophy in part through RhoA/ROCK (small GTPase/Rho-associated coiled-coil containing protein kinase) pathway. FHOD3 (formin homology 2 domain containing 3), a cardiac-restricted member of diaphanous-related formins, is crucial in regulating myofibrillogenesis in cardiomyocytes. FHOD3 maintains inactive through autoinhibition by an intramolecular interaction between its C- and N-terminal domains...
June 2017: Hypertension
https://www.readbyqxmd.com/read/28427457/integrative-modelling-of-tir-domain-containing-adaptor-molecule-inducing-interferon-%C3%AE-trif-provides-insights-into-its-autoinhibited-state
#9
Jarjapu Mahita, Ramanathan Sowdhamini
BACKGROUND: TRIF is a key protein in antiviral innate immunity, operating downstream of TLRs. TRIF activation leads to the production of interferon-β and pro-inflammatory cytokines. There is evidence from experiments to suggest that the N-terminal domain of TRIF binds to its TIR domain to avoid constitutive activation. However, no structure of a complex between the N-terminal domain and the TIR domain exists till date. The disordered nature of the region connecting the N-terminal domain and the TIR domain compounds the issue of elucidating the mechanism of autoinhibition of TRIF...
April 20, 2017: Biology Direct
https://www.readbyqxmd.com/read/28426203/tyrosine-kinase-activation-and-conformational-flexibility-lessons-from-src-family-tyrosine-kinases
#10
Yilin Meng, Matthew P Pond, Benoît Roux
Protein kinases are enzymes that catalyze the covalent transfer of the γ-phosphate of an adenosine triphosphate (ATP) molecule onto a tyrosine, serine, threonine, or histidine residue in the substrate and thus send a chemical signal to networks of downstream proteins. They are important cellular signaling enzymes that regulate cell growth, proliferation, metabolism, differentiation, and migration. Unregulated protein kinase activity is often associated with a wide range of diseases, therefore making protein kinases major therapeutic targets...
April 20, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/28425706/allosteric-autoinhibition-pathway-in-transcription-factor-erg-dynamics-network-and-mutant-experimental-evaluations
#11
Wei Ye, Tianle Qian, Hao Liu, Ray Luo, Hai-Feng Chen
Allosteric autoinhibition exists in many transcription factors. The ERG proteins exhibit autoinhibition on DNA binding by the C-terminal and N-terminal inhibitory domains (CID and NID). However, the autoinhibition mechanism and allosteric pathway of ERG are unknown. In this study we intend to elucidate the residue-level allosteric mechanism and pathway via a combined approach of computational and experimental analyses. Specifically computational residue-level fluctuation correlation data was analyzed to reveal detailed dynamics signatures in the allosteric autoinhibition process...
April 25, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28420739/the-dnak-chaperone-uses-different-mechanisms-to-promote-and-inhibit-replication-of-vibrio-cholerae-chromosome-2
#12
Jyoti K Jha, Mi Li, Rodolfo Ghirlando, Lisa M Miller Jenkins, Alexander Wlodawer, Dhruba Chattoraj
Replication of Vibrio cholerae chromosome 2 (Chr2) depends on molecular chaperone DnaK to facilitate binding of the initiator (RctB) to the replication origin. The binding occurs at two kinds of site, 12-mers and 39-mers, which promote and inhibit replication, respectively. Here we show that DnaK employs different mechanisms to enhance the two kinds of binding. We found that mutations in rctB that reduce DnaK binding also reduce 12-mer binding and initiation. The initiation defect is suppressed by second-site mutations that increase 12-mer binding only marginally...
April 18, 2017: MBio
https://www.readbyqxmd.com/read/28414322/parkin-phosphoubiquitin-complex-reveals-cryptic-ubiquitin-binding-site-required-for-rbr-ligase-activity
#13
Atul Kumar, Viduth K Chaugule, Tara E C Condos, Kathryn R Barber, Clare Johnson, Rachel Toth, Ramasubramanian Sundaramoorthy, Axel Knebel, Gary S Shaw, Helen Walden
RING-between-RING (RBR) E3 ligases are a class of ubiquitin ligases distinct from RING or HECT E3 ligases. An important RBR ligase is Parkin, mutations in which lead to early-onset hereditary Parkinsonism. Parkin and other RBR ligases share a catalytic RBR module but are usually autoinhibited and activated via distinct mechanisms. Recent insights into Parkin regulation predict large, unknown conformational changes during Parkin activation. However, current data on active RBR ligases reflect the absence of regulatory domains...
May 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28394326/intraflagellar-transport-dynein-is-autoinhibited-by-trapping-of-its-mechanical-and-track-binding-elements
#14
Katerina Toropova, Miroslav Mladenov, Anthony J Roberts
Cilia are multifunctional organelles that are constructed using intraflagellar transport (IFT) of cargo to and from their tip. It is widely held that the retrograde IFT motor, dynein-2, must be controlled in order to reach the ciliary tip and then unleashed to power the return journey. However, the mechanism is unknown. Here, we systematically define the mechanochemistry of human dynein-2 motors as monomers, dimers, and multimotor assemblies with kinesin-II. Combining these data with insights from single-particle EM, we discover that dynein-2 dimers are intrinsically autoinhibited...
May 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28383355/influence-of-cyp2c8-polymorphisms-on-imatinib-steady-state-trough-level-in-chronic-myeloid-leukemia-and-gastrointestinal-stromal-tumor-patients
#15
Michiel C Verboom, Loes Visser, Sander Kouwen, Jesse J Swen, Jeroen Diepstraten, Ward F Posthuma, Hans Gelderblom, Daniëlle van Lammeren, Erik B Wilms
Imatinib trough levels have been associated with its clinical effects. During chronic use of imatinib, CYP2C8 becomes an important metabolizing enzyme because of cytochrome P450 3A4 (CYP3A4) autoinhibition. Single nucleotide polymorphisms (SNPs) in CYP2C8 may affect imatinib trough levels. This study investigates the effect of common CYP2C8 polymorphisms [*1B (rs7909236), *1C (rs17110453), *3 (rs11572080 and rs10509681), and *4 (rs1058930)] on steady-state trough levels imatinib during chronic imatinib use in 43 patients with chronic myeloid leukemia or gastrointestinal stromal tumors...
June 2017: Pharmacogenetics and Genomics
https://www.readbyqxmd.com/read/28369120/fatty-acid-dsf-binds-and-allosterically-activates-histidine-kinase-rpfc-of-phytopathogenic-bacterium-xanthomonas-campestris-pv-campestris-to-regulate-quorum-sensing-and-virulence
#16
Zhen Cai, Zhi-Hui Yuan, Huan Zhang, Yue Pan, Yao Wu, Xiu-Qi Tian, Fang-Fang Wang, Li Wang, Wei Qian
As well as their importance to nutrition, fatty acids (FA) represent a unique group of quorum sensing chemicals that modulate the behavior of bacterial population in virulence. However, the way in which full-length, membrane-bound receptors biochemically detect FA remains unclear. Here, we provide genetic, enzymological and biophysical evidences to demonstrate that in the phytopathogenic bacterium Xanthomonas campestris pv. campestris, a medium-chain FA diffusible signal factor (DSF) binds directly to the N-terminal, 22 amino acid-length sensor region of a receptor histidine kinase (HK), RpfC...
April 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28348077/structural-and-thermodynamic-basis-of-a-frontometaphyseal-dysplasia-mutation-in-filamin-a
#17
Sujay S Ithychanda, Kevin Dou, Stephen P Robertson, Jun Qin
Filamin-mediated linkages between transmembrane receptors (TR) and the actin cytoskeleton are crucial for regulating many cytoskeleton-dependent cellular processes such as cell shape change and migration. A major TR binding site in the immunoglobulin repeat 21 (Ig21) of filamin is masked by the adjacent repeat Ig20 resulting in autoinhibition. The TR binding to this site triggers the relief of Ig20 and protein kinase A(PKA)-mediated phosphorylation of S2152, thereby dynamically regulating the TR-actin linkages...
March 27, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28347651/selective-targeting-of-sh2-domain-phosphotyrosine-interactions-of-src-family-tyrosine-kinases-with-monobodies
#18
Tim Kükenshöner, Nadine Eliane Schmit, Emilie Bouda, Fern Sha, Florence Pojer, Akiko Koide, Markus Seeliger, Shohei Koide, Oliver Hantschel
The binding of Src-homology 2 (SH2) domains to phosphotyrosine (pY) sites is critical for the autoinhibition and substrate recognition of the eight Src family kinases (SFKs). The high sequence conservation of the 120 human SH2 domains poses a significant challenge to selectively perturb the interactions of even the SFK SH2 family against the rest of the SH2 domains. We have developed synthetic binding proteins, termed monobodies, for six of the SFK SH2 domains with nanomolar affinity. Most of these monobodies competed with pY ligand binding and showed strong selectivity for either the SrcA (Yes, Src, Fyn, Fgr) or SrcB subgroup (Lck, Lyn, Blk, Hck)...
May 5, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28332566/a-conformational-change-within-the-wave2-complex-regulates-its-degradation-following-cellular-activation
#19
Noah Joseph, Guy Biber, Sophia Fried, Barak Reicher, Omer Levy, Batel Sabag, Elad Noy, Mira Barda-Saad
WASp family Verprolin-homologous protein-2 (WAVE2), a member of the Wiskott-Aldrich syndrome protein (WASp) family of actin nucleation promoting factors, is a central regulator of actin cytoskeleton polymerization and dynamics. Multiple signaling pathways operate via WAVE2 to promote the actin-nucleating activity of the actin-related protein 2/3 (Arp2/3) complex. WAVE2 exists as a part of a pentameric protein complex known as the WAVE regulatory complex (WRC), which is unstable in the absence of its individual proteins...
March 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28302907/skip-controls-lysosome-positioning-using-a-composite-kinesin-1-heavy-and-light-chain-binding-domain
#20
Anneri Sanger, Yan Y Yip, Thomas S Randall, Stefano Pernigo, Roberto A Steiner, Mark P Dodding
The molecular interplay between cargo recognition and regulation of the activity of the kinesin-1 microtubule motor is not well understood. Using the lysosome adaptor SKIP as model cargo, we show that the heavy chains (KHCs), in addition to the light chains (KLCs), can recognize tryptophan-acidic binding determinants on the cargo when presented in the context of an extended KHC interacting domain. Mutational separation of KHC and KLC binding shows that both interactions are important for SKIP-kinesin-1 interaction in vitro and that KHC binding is important for lysosome transport in vivo...
March 16, 2017: Journal of Cell Science
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