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Vishal A Salunkhe, Jones K Ofori, Nikhil R Gandasi, Sofia A Salö, Sofia Hansson, Markus E Andersson, Anna Wendt, Sebastian Barg, Jonathan L S Esguerra, Lena Eliasson
MicroRNAs contribute to the maintenance of optimal cellular functions by fine-tuning protein expression levels. In the pancreatic β-cells, imbalances in the exocytotic machinery components lead to impaired insulin secretion and type 2 diabetes (T2D). We hypothesize that dysregulated miRNA expression exacerbates β-cell dysfunction, and have earlier shown that islets from the diabetic GK-rat model have increased expression of miRNAs, including miR-335-5p (miR-335). Here, we aim to determine the specific role of miR-335 during development of T2D, and the influence of this miRNA on glucose-stimulated insulin secretion and Ca(2+)-dependent exocytosis...
November 2017: Physiological Reports
Colin P Johnson
The ferlin family of proteins have emerged as multi-C2 domain regulators of calcium triggered membrane fusion and fission events. While initially determined to share many of the features of the synaptotagmins family of calcium sensors, more recent studies have determined that ferlins directly interact with non-neuronal voltage gated calcium channels and nucleate the assembly of membrane trafficking protein complexes, functions that distinguish them from the more well studied synaptotagmins family. Here we highlight some of the recent findings that have advanced our understanding of ferlins and their functional differences with the synaptotagmins family...
November 7, 2017: Biochemistry
Elena Santana, Sergio Casas-Tintó
How synapses are built and dismantled is a central question in neurobiology. A wide range of proteins and processes from gene transcription to protein degradation are involved. Orb2 regulates mRNA translation depending on its monomeric or oligomeric state to modulate nervous system development and memory. Orb2 is expressed in Drosophila larval brain and neuromuscular junction (NMJ), Orb2 knockdown causes a reduction of synapse number and defects in neuronal morphology. Brain tumor (Brat) is an Orb2 target; it is expressed in larval brain related with cell growth and proliferation...
November 6, 2017: Journal of Neurogenetics
Yusuke Hirabayashi, Seok-Kyu Kwon, Hunki Paek, Wolfgang M Pernice, Maëla A Paul, Jinoh Lee, Parsa Erfani, Ashleigh Raczkowski, Donald S Petrey, Liza A Pon, Franck Polleux
Interfaces between organelles are emerging as critical platforms for many biological responses in eukaryotic cells. In yeast, the ERMES complex is an endoplasmic reticulum (ER)-mitochondria tether composed of four proteins, three of which contain a SMP (synaptotagmin-like mitochondrial-lipid binding protein) domain. No functional ortholog for any ERMES protein has been identified in metazoans. Here, we identified PDZD8 as an ER protein present at ER-mitochondria contacts. The SMP domain of PDZD8 is functionally orthologous to the SMP domain found in yeast Mmm1...
November 3, 2017: Science
Lu Ma, Yiying Cai, Yanghui Li, Junyi Jiao, Zhenyong Wu, Ben O'Shaughnessy, Pietro De Camilli, Erdem Karatekin, Yongli Zhang
Many biological processes rely on protein-membrane interactions in the presence of mechanical forces, yet high resolution methods to quantify such interactions are lacking. Here, we describe a single-molecule force spectroscopy approach to quantify membrane binding of C2 domains in Synaptotagmin-1 (Syt1) and Extended Synaptotagmin-2 (E-Syt2). Syts and E-Syts bind the plasma membrane via multiple C2 domains, bridging the plasma membrane with synaptic vesicles or endoplasmic reticulum to regulate membrane fusion or lipid exchange, respectively...
October 30, 2017: ELife
Hanbin Jeong, Jumi Park, Youngsoo Jun, Changwook Lee
The endoplasmic reticulum (ER)-mitochondria encounter structure (ERMES) comprises mitochondrial distribution and morphology 12 (Mdm12), maintenance of mitochondrial morphology 1 (Mmm1), Mdm34, and Mdm10 and mediates physical membrane contact sites and nonvesicular lipid trafficking between the ER and mitochondria in yeast. Herein, we report two crystal structures of the synaptotagmin-like mitochondrial lipid-binding protein (SMP) domain of Mmm1 and the Mdm12-Mmm1 complex at 2.8 Å and 3.8 Å resolution, respectively...
October 25, 2017: Proceedings of the National Academy of Sciences of the United States of America
Alexander M Walter, Rainer Müller, Bassam Tawfik, Keimpe Db Wierda, Paulo S Pinheiro, André Nadler, Anthony W McCarthy, Iwona Ziomkiewicz, Martin Kruse, Gregor Reither, Jens Rettig, Martin Lehmann, Volker Haucke, Bertil Hille, Carsten Schultz, Jakob Balslev Sorensen
Phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] is essential for exocytosis. Classical ways of manipulating PI(4,5)P2 levels are slower than metabolism, making it difficult to distinguish effects of PI(4,5)P2 from those of its metabolites. We developed a membrane-permeant, photoactivatable PI(4,5)P2, which is loaded into cells in an inactive form and activated by light, allowing sub-second increases in PI(4,5)P2 levels. By combining this compound with electrophysiological measurements in mouse adrenal chromaffin cells, we show that PI(4,5)P2 uncaging potentiates exocytosis and identify synaptotagmin-1 (the Ca(2+) sensor for exocytosis) and Munc13-2 (a vesicle priming protein) as the relevant effector proteins...
October 25, 2017: ELife
Zhenyong Wu, Sathish Thiyagarajan, Ben O'Shaughnessy, Erdem Karatekin
Calcium-triggered exocytotic release of neurotransmitters and hormones from neurons and neuroendocrine cells underlies neuronal communication, motor activity and endocrine functions. The core of the neuronal exocytotic machinery is composed of soluble N-ethyl maleimide sensitive factor attachment protein receptors (SNAREs). Formation of complexes between vesicle-attached v- and plasma-membrane anchored t-SNAREs in a highly regulated fashion brings the membranes into close apposition. Small, soluble proteins called Complexins (Cpx) and calcium-sensing Synaptotagmins cooperate to block fusion at low resting calcium concentrations, but trigger release upon calcium increase...
2017: Frontiers in Molecular Neuroscience
Anna Chiara Nascimbeni, Patrice Codogno, Etienne Morel
The biogenesis of autophagosome, the double membrane bound organelle related to macro-autophagy, is a complex event requiring numerous key-proteins and membrane remodeling events. Our recent findings identify the extended synaptotagmins, crucial tethers of Endoplasmic Reticulum-plasma membrane contact sites, as key-regulators of this molecular sequence.
2017: Molecular & Cellular Oncology
Imane El Kasmi, Bita Khadivjam, Miki Lackman, Johanne Duron, Eric Bonneil, Pierre Thibault, Roger Lippé
Enveloped viruses typically encode their own fusion machinery to enter cells. Herpesviruses are particular as they fuse with a number of cellular compartments throughout their life cycle. As the uncontrolled mixing of the host membranes should be avoided in these events, the tight regulation of the viral fusion machinery is critical. While studying the herpes simplex virus type 1 glycoprotein gM, we identified the cellular protein E-Syt1 (Extended synaptotagmin-1) as an interaction partner. This took place in both infected and transfected cells, suggesting other viral proteins were not required for this interaction...
October 18, 2017: Journal of Virology
Pengwei Wang, Chris Hawes, Christine Richardson, Patrick J Hussey
Like in most eukaryotic cells, the plant endoplasmic reticulum (ER) network is physically linked to the plasma membrane (PM), forming ER-PM contact sites (EPCS). The protein complex required for maintaining the EPCS is composed of ER integral membrane proteins (e.g., VAP27, synaptotagmins), PM-associated proteins (e.g., NET3C), and the cytoskeleton. Here, we describe methods for identifying possible EPCS-associated proteins. These include GFP-tagged protein expression followed by image analysis, and immuno-gold labeling at the ultrastructural level...
2018: Methods in Molecular Biology
Adam J Trexler, Justin W Taraska
The control of insulin release from pancreatic beta cells helps ensure proper blood glucose level, which is critical for human health. Protein kinase C has been shown to be one key control mechanism for this process. After glucose stimulation, calcium influx into beta cells triggers exocytosis of insulin-containing dense-core granules and activates protein kinase C via calcium-dependent phospholipase C-mediated generation of diacylglycerol. Activated protein kinase C potentiates insulin release by enhancing the calcium sensitivity of exocytosis, likely by affecting two main pathways that could be linked: (1) the reorganization of the cortical actin network, and (2) the direct phosphorylation of critical exocytotic proteins such as munc18, SNAP25, and synaptotagmin...
November 2017: Cell Calcium
Pathomwat Wongrattanakamon, Piyarat Nimmanpipug, Busaban Sirithunyalug, Supat Jiranusornkul
Synaptotagmin 1 (Syt1) is the Ca(2+) sensor protein with an essential role in neurotransmitter release. Since the wrinkle formation is due to the excessive muscle fiber stimulation in the face, a helpful stratagem to diminish the wrinkle line intenseness is to weaken the innervating neuron activity through Syt1 inhibition which is one of the possible therapeutic strategies against wrinkles. Recently, experimental evidence showed that botox-like peptides, which are typically used as SNARE modulators, may inhibit Syt1...
October 10, 2017: Molecular and Cellular Biochemistry
Bing Xiao, Jianbin Li, Yanghua Fan, Minhua Ye, Shigang Lv, Bin Xu, Yi Chai, Zhiqing Zhou, Miaojing Wu, Xingen Zhu
Synaptotagmin‑7 (SYT7) is a member of the synaptotagmin gene family, and encodes a protein that mediates the calcium‑dependent regulation of membrane trafficking during synaptic transmission. A previous study demonstrated that the expression of SYT7 is associated with prostate cancer and serves an important role in development of prostate cancer. However, the roles of SYT7 in the progression of glioma remain unknown. In the present study, reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) analysis demonstrated that SYT7 was expressed in three human glioma cell lines...
December 2017: Molecular Medicine Reports
Deborah A Court, Shivani Khetoo, Sabbir R Shuvo, Shayne D Reitmeier, Georg Hausner
In eukaryotic cells, communication and dynamic interactions among different organelles are important for maintaining cellular homeostasis. The endoplasmic reticulum (ER) mitochondria encounter structure (ERMES) complex establishes membrane contact sites between ER and mitochondria and is essential for phospholipid transport, protein import, and mitochondrial dynamics and inheritance. In this work, in silico analyses were used to probe the intramolecular interactions in ERMES proteins and the interactions that support the ERMES complex...
October 6, 2017: Canadian Journal of Microbiology
James E Rothman, Shyam S Krishnakumar, Kirill Grushin, Frederic Pincet
Neural networks are optimized to detect temporal coincidence on the millisecond timescale. Here, we offer a synthetic hypothesis based on recent structural insights into SNAREs and the C2 domain proteins to explain how synaptic transmission can keep this pace. We suggest that an outer ring of up to six curved Munc13 'MUN' domains transiently anchored to the plasma membrane via its flanking domains surrounds a stable inner ring comprised of synaptotagmin C2 domains to serve as a work-bench on which SNAREpins are templated...
October 6, 2017: FEBS Letters
Mallory C Shields, Matthew R Bowers, McKenzie M Fulcer, Madelyn K Bollig, Patrick J Rock, Bryan R Sutton, Alysia D Vrailas-Mortimer, Hanns Lochmüller, Roger G Whittaker, Rita Horvath, Noreen E Reist
During chemical transmission, the function of synaptic proteins must be coordinated to efficiently release neurotransmitter. Synaptotagmin 2, the Ca2+ sensor for fast, synchronized neurotransmitter release at the human neuromuscular junction, has recently been implicated in a dominantly inherited congenital myasthenic syndrome associated with a non-progressive motor neuropathy. In one family, a proline residue within the C2B Ca2+-binding pocket of synaptotagmin is replaced by a leucine. The functional significance of this residue has not been investigated previously...
2017: PloS One
Rui Huang, Jin Zhao, Jin Liu, Yingdian Wang, Shengcheng Han, Heping Zhao
N-terminal-TM-C2 domain proteins (NTMC2), which share domain architecture and sequence similarity to synaptotagmins (Syts) in mammals and FAM62 (extended Syts) in metazoans, form a small gene family in plants. Previous studies showed that the Arabidopsis thaliana NTMC2 type 1.1 protein (NTMC2T1.1, named AtSyt1) possesses calcium- and membrane-binding activities that allow it to function in a plasma membrane repair pathway induced by stress. However, we lack understanding of the diverse biological roles of plant NTMC2 family genes...
September 22, 2017: Gene
Ran Li, Srinivas Chiguru, Li Li, Dongyoung Kim, Ramraj Velmurugan, David Kim, Siva Charan Devanaboyina, Hong Tian, Alan Schroit, Ralph Mason, Raimund J Ober, E Sally Ward
In response to cellular stress, phosphatidylserine (PS) is exposed on the outer membrane leaflet of tumor blood vessels and cancer cells, motivating the development of PS-specific therapies. The generation of drug-conjugated PS-targeting agents represents an unexplored therapeutic approach, for which anti-tumor effects are critically dependent on efficient internalization and lysosomal delivery of the cytotoxic drug. In the current study, we have generated PS-targeting agents by fusing PS-binding domains to a human IgG1-derived Fc fragment...
September 22, 2017: Molecular Cancer Therapeutics
Rashmi Voleti, Diana R Tomchick, Thomas C Südhof, Josep Rizo
Synaptotagmins (Syts) act as Ca(2+) sensors in neurotransmitter release by virtue of Ca(2+)-binding to their two C2 domains, but their mechanisms of action remain unclear. Puzzlingly, Ca(2+)-binding to the C2B domain appears to dominate Syt1 function in synchronous release, whereas Ca(2+)-binding to the C2A domain mediates Syt7 function in asynchronous release. Here we show that crystal structures of the Syt7 C2A domain and C2AB region, and analyses of intrinsic Ca(2+)-binding to the Syt7 C2 domains using isothermal titration calorimetry, did not reveal major differences that could explain functional differentiation between Syt7 and Syt1...
October 3, 2017: Proceedings of the National Academy of Sciences of the United States of America
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