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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
#1
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
#2
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...
July 18, 2017: Bioorganic Chemistry
https://www.readbyqxmd.com/read/28772122/a-c1-c2-module-in-munc13-inhibits-calcium-dependent-neurotransmitter-release
#3
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
https://www.readbyqxmd.com/read/28772115/unc13-aligns-snares-and-superprimes-synaptic-vesicles
#4
Mark T Palfreyman, Erik M Jorgensen
Unc13 proteins are required for vesicle docking and priming during exocytosis. In this issue of Neuron, Lai et al. (2017) demonstrate that Unc13 ensures that the SNAREs assemble into functional subcomplexes. In a second manuscript, Michelassi et al. (2017) identify a previously unknown autoinhibited state for Unc13 mediated by the tandem C1 and C2 domains.
August 2, 2017: Neuron
https://www.readbyqxmd.com/read/28765284/structural-basis-of-autoinhibition-and-activation-of-the-dna-targeting-adp-ribosyltransferase-pierisin-1
#5
Takashi Oda, Hirokazu Hirabayashi, Gen Shikauchi, Ryouma Takamura, Kiyoshi Hiraga, Hiroshi Minami, Hiroshi Hashimoto, Masafumi Yamamoto, Keiji Wakabayashi, Toshiyuki Shimizu, Mamoru Sato
ADP-ribosyltransferases transfer the ADP-ribose moiety of βNAD+ to an acceptor molecule, usually a protein that modulates the function of the acceptor. Pierisin-1 is an ADP-ribosyltransferase from the cabbage butterfly Pieris rapae and is composed of N-terminal catalytic and C-terminal Ricin B-like domains. Curiously, it ADP-ribosylates the DNA duplex, resulting in apoptosis of various cancer cells, which has raised interest in pierisin-1 as an anti-cancer agent. However, both the structure and the mechanism of DNA ADP-ribosylation are unclear...
August 1, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28728983/etv4-and-ap1-transcription-factors-form-multivalent-interactions-with-three-sites-on-the-med25-activator-interacting-domain
#6
Simon L Currie, Jedediah J Doane, Kathryn S Evans, Niraja Bhachech, Bethany J Madison, Desmond K W Lau, Lawrence P McIntosh, Jack J Skalicky, Kathleen A Clark, Barbara J Graves
The recruitment of transcriptional cofactors by sequence-specific transcription factors challenges the basis of high affinity and selective interactions. Extending previous studies that the N-terminal activation domain (AD) of ETV5 interacts with Mediator subunit 25 (MED25), we establish that similar, aromatic-rich motifs located both in the AD and in the DNA-binding domain (DBD) of the related ETS factor ETV4 interact with MED25. These ETV4 regions bind MED25 independently, display distinct kinetics, and combine to contribute to a high-affinity interaction of full-length ETV4 with MED25...
July 17, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28724794/apol1-variants-change-c-terminal-conformational-dynamics-and-binding-to-snare-protein-vamp8
#7
Sethu M Madhavan, John F O'Toole, Martha Konieczkowski, Laura Barisoni, David B Thomas, Santhi Ganesan, Leslie A Bruggeman, Matthias Buck, John R Sedor
APOL1 variants in African populations mediate resistance to trypanosomal infection but increase risk for kidney diseases through unknown mechanisms. APOL1 is expressed in glomerular podocytes and does not vary with underlying kidney disease diagnoses or APOL1 genotypes, suggesting that the kidney disease-associated variants dysregulate its function rather than its localization or abundance. Structural homology searches identified vesicle-associated membrane protein 8 (VAMP8) as an APOL1 protein interactor. VAMP8 colocalizes with APOL1 in the podocyte, and the APOL1:VAMP8 interaction was confirmed biochemically and with surface plasmon resonance...
July 20, 2017: JCI Insight
https://www.readbyqxmd.com/read/28701352/calcium-pumps-and-interacting-bon1-protein-modulate-calcium-signature-stomatal-closure-and-plant-immunity
#8
Dong-Lei Yang, Zhenying Shi, Yongmei Bao, Jiapei Yan, Ziyuan Yang, Huiyun Yu, Yun Li, Mingyue Gou, Shu Wang, Baohong Zou, Dachao Xu, Zhiqi Ma, Jitae Kim, Jian Hua
Calcium signaling is essential for environmental responses including immune responses. Here we provide evidence that the evolutionarily conserved protein BONZAI1 (BON1) functions together with autoinhibited calcium ATPase 10 (ACA10) and ACA8 to regulate calcium signals in Arabidopsis. BON1 is a plasma membrane localized protein that negatively regulates the expression of immune receptor genes and positively regulates stomatal closure. We found that BON1 interacts with the autoinhibitory domains of ACA10 and ACA8, and the aca10 loss of function (LOF) mutants have an autoimmune phenotype similar to that of the bon1 LOF mutants...
July 12, 2017: Plant Physiology
https://www.readbyqxmd.com/read/28689178/sacubitril-valsartan-beyond-natriuretic-peptides
#9
REVIEW
Jagdeep S S Singh, Louise M Burrell, Myriam Cherif, Iain B Squire, Andrew L Clark, Chim C Lang
Natriuretic peptides, especially B-type natriuretic peptide (BNP), have primarily been regarded as biomarkers in heart failure (HF). However, they are also possible therapeutic agents due to their potentially beneficial physiological effects. The angiotensin receptor-neprilysin inhibitor, sacubitril/valsartan, simultaneously augments the natriuretic peptide system (NPS) by inhibiting the enzyme neprilysin (NEP) and inhibits the renin-angiotensin-aldosterone system (RAAS) by blocking the angiotensin II receptor...
July 8, 2017: Heart: Official Journal of the British Cardiac Society
https://www.readbyqxmd.com/read/28638935/jip1-and-jip3-cooperate-to-mediate-trkb-anterograde-axonal-transport-by-activating-kinesin-1
#10
Tao Sun, Yuan Li, Ting Li, Huixian Ma, Yunyun Guo, Xingyu Jiang, Ming Hou, Shuhong Huang, Zheyu Chen
Long-range anterograde axonal transport of TrkB is important for neurons to exert appropriate BDNF responses. TrkB anterograde axonal delivery is mediated by kinesin-1, which associates with TrkB via the adaptor protein JIP3 or the Slp1/Rab27B/CRMP-2 protein complex. However, little is known about the activation mechanisms of TrkB-loaded kinesin-1. Here, we show that JIP1 mediates TrkB anterograde axonal transport using JIP1 knockout mice, sciatic nerve ligation analysis and live imaging. Next, we proved that JIP1 and JIP3 cooperate to mediate TrkB anterograde axonal transport...
June 21, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28620171/mechanical-stability-of-talin-rod-controls-cell-migration-and-substrate-sensing
#11
Rolle Rahikainen, Magdaléna von Essen, Markus Schaefer, Lei Qi, Latifeh Azizi, Conor Kelly, Teemu O Ihalainen, Bernhard Wehrle-Haller, Martin Bastmeyer, Cai Huang, Vesa P Hytönen
Cells adhere to the surrounding tissue and probe its mechanical properties by forming cell-matrix adhesions. Talin is a critical adhesion protein and participates in the transmission of mechanical signals between extracellular matrix and cell cytoskeleton. Force induced unfolding of talin rod subdomains has been proposed to act as a cellular mechanosensor, but so far evidence linking their mechanical stability and cellular response has been lacking. Here, by utilizing computationally designed mutations, we demonstrate that stepwise destabilization of the talin rod R3 subdomain decreases cellular traction force generation, which affects talin and vinculin dynamics in cell-matrix adhesions and results in the formation of talin-rich but unstable adhesions...
June 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28607149/polycomb-repressive-complex-2-in-an-autoinhibited-state
#12
Matthew Bratkowski, Xin Yang, Xin Liu
Polycomb-group proteins control many fundamental biological processes, such as anatomical development in mammals and vernalization in plants. Polycomb repressive complex 2 (PRC2) is responsible for methylation of histone H3 lysine 27 (H3K27), and trimethylated H3K27 (H3K27me3) is implicated in epigenetic gene silencing. Recent genomic, biochemical, and structural data indicate that PRC2 is broadly conserved from yeast to human in many aspects. Here, we determined the crystal structure of an apo-PRC2 from the fungus Chaetomium thermophilum captured in a bona fide autoinhibited state, which represents a novel conformation of PRC2 associated with enzyme regulation in light of the basal and stimulated states that we reported previously...
August 11, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28576829/differential-effects-of-the-dynein-regulatory-factor-lissencephaly-1-on-processive-dynein-dynactin-motility
#13
COMPARATIVE STUDY
Pedro A Gutierrez, Bryce E Ackermann, Michael Vershinin, Richard J McKenney
Cytoplasmic dynein is the primary minus-end-directed microtubule motor protein in animal cells, performing a wide range of motile activities, including transport of vesicular cargos, mRNAs, viruses, and proteins. Lissencephaly-1 (LIS1) is a highly conserved dynein-regulatory factor that binds directly to the dynein motor domain, uncoupling the enzymatic and mechanical cycles of the motor and stalling dynein on the microtubule track. Dynactin, another ubiquitous dynein-regulatory factor, releases dynein from an autoinhibited state, leading to a dramatic increase in fast, processive dynein motility...
July 21, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28548966/targeting-shp-1-stat3-signaling-a-promising-therapeutic-approach-for-the-treatment-of-cholangiocarcinoma
#14
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...
May 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28541184/the-step-wise-pathway-of-septin-hetero-octamer-assembly-in-budding-yeast
#15
Andrew Weems, Michael McMurray
Septin proteins bind guanine nucleotides and form rod-shaped hetero-oligomers. Cells choose from a variety of available septins to assemble distinct hetero-oligomers, but the underlying mechanism was unknown. Using a new in vivo assay, we find that a stepwise assembly pathway produces the two species of budding yeast septin hetero-octamers: Cdc11/Shs1-Cdc12-Cdc3-Cdc10-Cdc10-Cdc3-Cdc12-Cdc11/Shs1. Rapid GTP hydrolysis by monomeric Cdc10 drives assembly of the core Cdc10 homodimer. The extended Cdc3 N terminus autoinhibits Cdc3 association with Cdc10 homodimers until prior Cdc3-Cdc12 interaction...
May 25, 2017: ELife
https://www.readbyqxmd.com/read/28537552/structure-analyses-reveal-a-regulated-oligomerization-mechanism-of-the-plexind1-gipc-myosin-vi-complex
#16
Guijun Shang, Chad A Brautigam, Rui Chen, Defen Lu, Jesús Torres-Vázquez, Xuewu Zhang
The GIPC family adaptor proteins mediate endocytosis by tethering cargo proteins to the myosin VI motor. The structural mechanisms for the GIPC/cargo and GIPC/myosin VI interactions remained unclear. PlexinD1, a transmembrane receptor that regulates neuronal and cardiovascular development, is a cargo of GIPCs. GIPC-mediated endocytic trafficking regulates PlexinD1 signaling. Here, we unravel the mechanisms of the interactions among PlexinD1, GIPCs and myosin VI by a series of crystal structures of these proteins in apo or bound states...
May 24, 2017: ELife
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
#17
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
#18
(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
#19
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 preformed 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
#20
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
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