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Tethering complex

Yi-Shu Huang, Nien-Yi Chiang, Gin-Wen Chang, Hsi-Hsien Lin
The evolutionarily conserved adhesion G protein-coupled receptors (aGPCRs) play critical roles in biological processes as diverse as brain development, cell polarity and innate immune functions. A defining feature of aGPCRs is the GPCR autoproteolysis inducing (GAIN) domain capable of self-catalytic cleavage, resulting in the generation of an extracellular N-terminal fragment (NTF) and a seven-transmembrane C-terminal fragment (CTF) involved in the cellular adhesion and signaling functions, respectively. Interestingly, two different NTF subtypes have previously been identified, namely an NTF that couples non-covalently with the CTF and a membrane-associated NTF that tethers on cell surface independently...
March 14, 2018: Scientific Reports
Tomohiro Kubo, Yuqing Hou, Deborah A Cochran, George B Witman, Toshiyuki Oda
Motility of cilia/flagella is generated by a coordinated activity of thousands of dyneins. Inner dynein arms (IDAs) are particularly important for the formation of ciliary/flagellar waveforms, but the molecular mechanism of IDA regulation is poorly understood. Here, we show using cryo-electron tomography and biochemical analyses of Chlamydomonas flagella that a conserved protein FAP44 forms a complex that tethers IDA f (I1 dynein) head domains to the A-tubule of the axonemal outer doublet microtubule. In wild-type flagella, IDA f showed little nucleotide-dependent movement except for a tilt in the f β head perpendicular to the microtubule-sliding direction...
March 14, 2018: Molecular Biology of the Cell
Weiwei Lin, Hongtao Xu, Guman Duan, Jinjin Xie, Yisheng Chen, Baohua Jiao, Haitao Lan
Purpose Tethered cord syndrome (TCS) is the clinical manifestation of an abnormal stretch on the spinal cord, caused by several pathological conditions. Tethered cord release is the gold standard treatment for TCS. However, direct untethering carries potential risks of spinal cord injury, post-operative retethering, and CSF-related complications. Spine-shortening osteotomy (SSO) has recently been performed as an alternative technique to avoid these risks. We aimed to systematically review the literature on indications and outcome of SSO in TCS patients...
March 12, 2018: Neurological Research
Hyun Ju Lim, Zara Khan, Xi Lu, T Hiran Perera, Thomas S Wilems, Krishna T Ravivarapu, Laura A Smith Callahan
Balancing enhancement of neurite extension against loss of matrix support in synthetic hydrogels containing proteolytically degradable and bioactive signaling peptides to optimize tissue formation is difficult. Using a systematic approach, polyethylene glycol hydrogels containing concurrent continuous concentration gradients of the laminin derived bioactive signaling peptide, Ile-Lys-Val-Ala-Val (IKVAV), and collagen derived matrix metalloprotease degradable peptide, GPQGIWGQ, were fabricated and characterized...
March 8, 2018: Acta Biomaterialia
E M Peter-Ross
The pathobiological causes, the shared cellular and molecular pathways in catatonia and in catatonic presentation in neuropsychiatric disorders are yet to be determined. The hypotheses in this paper have been deduced from the latest scientific research findings and clinical observations of patients with genetic disorders, behavioral phenotypes and other family members suffering mental disorders. The first hypothesis postulates that catatonia and the heterogeneity of catatonic signs and symptoms involve nucleolar dysfunction arising from abnormalities of the brain-specific, non-coding micro-RNA, SNORD115 genes (either duplications or deletions) which result in pathobiological dysfunction of various combinations in the downstream pathways (possibly along with other genes in these shared pathways)...
April 2018: Medical Hypotheses
Molly C Sutherland, Joshua M Jarodsky, Sergey Ovchinnikov, David Baker, Robert G Kranz
Although many putative heme transporters have been discovered, it has been challenging to prove that these proteins are directly involved with heme trafficking in vivo and to identify their heme binding domains. The prokaryotic pathways for cytochrome c biogenesis, Systems I and II, transport heme from inside the cell to outside for stereochemical attachment to cytochrome c, making them excellent models to study heme trafficking. System I is composed of eight integral membrane proteins (CcmA-H) and is proposed to transport heme via CcmC to an external "WWD" domain for presentation to the membrane-tethered heme chaperone, CcmE...
March 5, 2018: Journal of Molecular Biology
Jessika C Bridi, Frank Hirth
Parkinson's disease (PD) is characterized by intracellular inclusions of aggregated and misfolded α-Synuclein (α-Syn), and the loss of dopaminergic (DA) neurons in the brain. The resulting motor abnormalities mark the progression of PD, while non-motor symptoms can already be identified during early, prodromal stages of disease. Recent studies provide evidence that during this early prodromal phase, synaptic and axonal abnormalities occur before the degenerative loss of neuronal cell bodies. These early phenotypes can be attributed to synaptic accumulation of toxic α-Syn...
2018: Frontiers in Neuroscience
Gang Fu, Qian Wang, Nhan Phan, Paulina Urbanska, Ewa Joachimiak, Jianfeng Lin, Dorota Wloga, Daniela Nicastro
Motile cilia are essential for propelling cells and moving fluids across tissues. The activity of axonemal dynein motors must be precisely coordinated to generate ciliary motility, but their regulatory mechanisms are not well understood. The tether and tether head (T/TH) complex was hypothesized to provide mechanical feedback during ciliary beating because it links the motor domains of the regulatory I1 dynein to the ciliary doublet microtubule. Combining genetic and biochemical approaches with cryo-electron tomography, we identified FAP44 and FAP43 (plus the algae-specific, FAP43-redundant FAP244) as T/TH components...
March 7, 2018: Molecular Biology of the Cell
Ishier Raote, Maria Ortega-Bellido, António J M Santos, Ombretta Foresti, Chong Zhang, Maria F Garcia-Parajo, Felix Campelo, Vivek Malhotra
Collagen export from the endoplasmic reticulum (ER) requires TANGO1, COPII coats, and retrograde fusion of ERGIC membranes. How do these components come together to produce a transport carrier commensurate with the bulky cargo collagen? TANGO1 is known to form a ring that corrals COPII coats and we show here how this ring or fence is assembled. Our data reveal that a TANGO1 ring is organized by its radial interaction with COPII, and lateral interactions with cTAGE5, TANGO1-short or itself. Of particular interest is the finding that TANGO1 recruits ERGIC membranes for collagen export via the NRZ (<u>N</u>BAS/<u>R</u>INT1/<u>Z</u>W10) tether complex...
March 7, 2018: ELife
Krister Wiklund, Hanqing Zhang, Tim Stangner, Bhupender Singh, Esther Bullitt, Magnus Andersson
We report an interpolation model to calculate the hydrodynamic force on tethered capsule-shaped cells in micro-fluidic flows near a surface. Our model is based on numerical solutions of the full Navier-Stokes equations for capsule-shaped objects considering their geometry, aspect ratio and orientation with respect to fluid flow. The model reproduced the results from computational fluid dynamic simulations, with an average error of <0.15 % for objects with an aspect ratio up to 5, and the model exactly reproduced the Goldman approximation of spherical objects close to a surface...
March 6, 2018: Microbiology
Ying Liu, Tuhin Bhowmick, Yiqiong Liu, Xuefan Gao, Haydyn D T Mertens, Dmitri I Svergun, Junyu Xiao, Yan Zhang, Jia-Huai Wang, Rob Meijers
Axon guidance involves the spatiotemporal interplay between guidance cues and membrane-bound cell-surface receptors, present on the growth cone of the axon. Netrin-1 is a prototypical guidance cue that binds to deleted in colorectal cancer (DCC), and it has been proposed that the guidance cue Draxin modulates this interaction. Here, we present structural snapshots of Draxin/DCC and Draxin/Netrin-1 complexes, revealing a triangular relationship that affects Netrin-mediated haptotaxis and fasciculation. Draxin interacts with DCC through the N-terminal four immunoglobulin domains, and Netrin-1 through the EGF-3 domain, in the same region where DCC binds...
February 20, 2018: Neuron
Fabio Cerignoli, Yama A Abassi, Brandon J Lamarche, Garret Guenther, David Santa Ana, Diana Guimet, Wen Zhang, Jing Zhang, Biao Xi
A growing understanding of the molecular interactions between immune effector cells and target tumor cells, coupled with refined gene therapy approaches, are giving rise to novel cancer immunotherapeutics with remarkable efficacy in the clinic against both solid and liquid tumors. While immunotherapy holds tremendous promise for treatment of certain cancers, significant challenges remain in the clinical translation to many other types of cancers and also in minimizing adverse effects. Therefore, there is an urgent need for functional potency assays, in vitro and in vivo, that could model the complex interaction of immune cells with tumor cells and can be used to rapidly test the efficacy of different immunotherapy approaches, whether it is small molecule, biologics, cell therapies or combinations thereof...
2018: PloS One
Rosanne L Rademaker, Young Eun Park, Alexander T Sack, Frank Tong
Previous studies have suggested that people can maintain prioritized items in visual working memory for many seconds, with negligible loss of information over time. Such findings imply that working memory representations are robust to the potential contaminating effects of internal noise. However, once visual information is encoded into working memory, one might expect it to inevitably begin degrading over time, as this actively maintained information is no longer tethered to the original perceptual input. Here, we examined this issue by evaluating working memory for single central presentations of an oriented grating, color patch, or face stimulus, across a range of delay periods (1, 3, 6, or 12 s)...
March 1, 2018: Journal of Experimental Psychology. Human Perception and Performance
Vaikundamoorthy Ramalingam, Krishnamoorthy Varunkumar, Vilwanathan Ravikumar, Rajendran Rajaram
Development of drug delivery system conjugated with doxorubicin (dox) on the surface of AuNPs with polyvinylpyrrolidone (Dox@PVP-AuNPs), we have demonstrated that human lung cancer cells can significantly overcome by the combination of highly effective cellular entry and responsive intracellular release of doxorubicin from Dox@PVP-AuNPs complex. Previously drug release from doxorubicin-conjugated AuNPs was confirmed by the recovered fluorescence of doxorubicin from quenching due to the nanosurface energy transfer between doxorubicinyl groups and AuNPs...
February 28, 2018: Scientific Reports
Manuela Aseye Ayele Ayee, Elizabeth LeMaster, Tao Teng, James Lee, Irena Levitan
Regulation of cell volume is a fundamental property of all mammalian cells. Multiple signaling pathways are known to be activated by cell swelling and to contribute to cell volume homeostasis. Although cell mechanics and membrane tension have been proposed to couple cell swelling to signaling pathways, the impact of swelling on cellular biomechanics and membrane tension have yet to be fully elucidated. In this study, we use atomic force microscopy under isotonic and hypotonic conditions to measure mechanical properties of endothelial membranes including membrane stiffness, which reflects the stiffness of the submembrane cytoskeleton complex, and the force required for membrane tether formation, reflecting membrane tension and membrane-cytoskeleton attachment...
February 27, 2018: Biophysical Journal
Liming Yan, Yuanbo Qi, Xiaofang Huang, Caiting Yu, Lan Lan, Xiangyang Guo, Zihe Rao, Junjie Hu, Zhiyong Lou
Fusion of the outer mitochondrial membrane is mediated by the dynamin-like GTPase mitofusin (MFN). Here, we determined the structure of the minimal GTPase domain (MGD) of human MFN1 in complex with GDP-BeF3 - . The MGD folds into a canonical GTPase fold with an associating four-helix bundle, HB1, and forms a dimer. A potassium ion in the catalytic core engages GDP and BeF3 - (GDP-BeF3 - ). Enzymatic analysis has confirmed that efficient GTP hydrolysis by MFN1 requires potassium. Compared to previously reported MGD structures, the HB1 structure undergoes a major conformational change relative to the GTPase domains, as they move from pointing in opposite directions to point in the same direction, suggesting that a swing of the four-helix bundle can pull tethered membranes closer to achieve fusion...
February 26, 2018: Nature Structural & Molecular Biology
Doreen Könning, Harald Kolmar
Pioneered exactly 20 years ago, yeast surface display (YSD) continues to take a major role in protein engineering among the high-throughput display methodologies that have been developed to date. The classical yeast display technology relies on tethering an engineered protein to the cell wall by genetic fusion to one subunit of a dimeric yeast-mating agglutination receptor complex. This method enables an efficient genotype-phenotype linkage while exploiting the benefits of a eukaryotic expression machinery...
February 26, 2018: Microbial Cell Factories
Andrea Coluccio, Gabriela Ecco, Julien Duc, Sandra Offner, Priscilla Turelli, Didier Trono
BACKGROUND: The KZFP/KAP1 (KRAB zinc finger proteins/KRAB-associated protein 1) system plays a central role in repressing transposable elements (TEs) and maintaining parent-of-origin DNA methylation at imprinting control regions (ICRs) during the wave of genome-wide reprogramming that precedes implantation. In naïve murine embryonic stem cells (mESCs), the genome is maintained highly hypomethylated by a combination of TET-mediated active demethylation and lack of de novo methylation, yet KAP1 is tethered by sequence-specific KZFPs to ICRs and TEs where it recruits histone and DNA methyltransferases to impose heterochromatin formation and DNA methylation...
February 26, 2018: Epigenetics & Chromatin
Gregory Craven, Dominic Affron, Charlotte Allen, Stefan Matthies, Joe Greener, Rhodri Morgan, Edward Tate, Alan Armstrong, David J Mann
Cysteine-reactive small molecules are used as chemical probes of biological systems and as medicines. Identifying high-quality covalent ligands requires comprehensive kinetic analysis to distinguish selective binders from pan-reactive compounds. Here we describe quantitative irreversible tethering (qIT), a general method for screening cysteine-reactive small molecules based upon the maximization of kinetic selectivity. We apply this method prospectively to discover covalent fragments that target the clinically important cell cycle regulator Cdk2...
February 26, 2018: Angewandte Chemie
Chen-Song Zhang, Mengqi Li, Yue Zong, Sheng-Cai Lin
Recent studies have revealed how AMPK is activated inside the cell and animal tissues: in response to low glucose, AXIN tethers LKB1, by virtue of their constitutive association, to AMPK located on the surface of late endosome/lysosome. Importantly, the lysosomal v-ATPase (vacuolar ATPase)-Ragulator complex, when primed by glucose starvation or concanamycin A, facilitates AXIN/LKB1 to interact with AMPK. Here, we describe the experimental procedures of the assays for detecting the translocation of AXIN/LKB1 or the assembly of the AXIN-based AMPK-activating complexes on the late endosome/lysosome...
2018: Methods in Molecular Biology
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