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  1. Article ; Online: Concurrent binding of complexin and synaptotagmin to liposome-embedded SNARE complexes.

    Chicka, Michael C / Chapman, Edwin R

    Biochemistry

    2009  Volume 48, Issue 4, Page(s) 657–659

    Abstract: Synaptotagmin and complexin regulate SNARE-mediated synaptic vesicle exocytosis. It has been proposed that complexin clamps membrane fusion and that Ca(2+)-synaptotagmin displaces complexin from SNARE complexes to relieve this clamping activity. Using a ... ...

    Abstract Synaptotagmin and complexin regulate SNARE-mediated synaptic vesicle exocytosis. It has been proposed that complexin clamps membrane fusion and that Ca(2+)-synaptotagmin displaces complexin from SNARE complexes to relieve this clamping activity. Using a reconstituted system, we demonstrate that complexin and synaptotagmin simultaneously bind to neuronal SNARE complexes and that both apo-synaptotagmin and complexin inhibit SNARE-mediated membrane fusion. Moreover, the clamping ability of apo-synaptotagmin occluded the clamping activity of complexin until the arrival of a Ca(2+) trigger, at which point synaptotagmin accelerated fusion while high concentrations of complexin inhibited fusion. Thus, the inhibitory patterns of synaptotagmin and complexin are different, suggesting that SNAREs assemble into distinct states along the fusion pathway. These data also suggest that during synaptotagmin-regulated vesicle-vesicle fusion, complexin does not function as a fusion clamp that is relieved by Ca(2+)-synaptotagmin.
    MeSH term(s) Adaptor Proteins, Vesicular Transport ; Animals ; Humans ; Liposomes/chemistry ; Liposomes/metabolism ; Nerve Tissue Proteins/chemistry ; Nerve Tissue Proteins/metabolism ; Protein Binding/physiology ; SNARE Proteins/chemistry ; SNARE Proteins/metabolism ; Synaptotagmins/chemistry ; Synaptotagmins/metabolism
    Chemical Substances Adaptor Proteins, Vesicular Transport ; Liposomes ; Nerve Tissue Proteins ; SNARE Proteins ; complexin I ; complexin II ; Synaptotagmins (134193-27-4)
    Language English
    Publishing date 2009-01-06
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1108-3
    ISSN 1520-4995 ; 0006-2960
    ISSN (online) 1520-4995
    ISSN 0006-2960
    DOI 10.1021/bi801962d
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  2. Article ; Online: Role of Munc13-4 as a Ca2+-dependent tether during platelet secretion.

    Chicka, Michael C / Ren, Qiansheng / Richards, David / Hellman, Lance M / Zhang, Jinchao / Fried, Michael G / Whiteheart, Sidney W

    The Biochemical journal

    2016  Volume 473, Issue 5, Page(s) 627–639

    Abstract: The Munc13 family of exocytosis regulators has multiple Ca(2+)-binding, C2 domains. Here, we probed the mechanism by which Munc13-4 regulates in vitro membrane fusion and platelet exocytosis. We show that Munc13-4 enhances in vitro soluble NSF attachment ...

    Abstract The Munc13 family of exocytosis regulators has multiple Ca(2+)-binding, C2 domains. Here, we probed the mechanism by which Munc13-4 regulates in vitro membrane fusion and platelet exocytosis. We show that Munc13-4 enhances in vitro soluble NSF attachment protein receptor (SNARE)-dependent, proteoliposome fusion in a Ca(2+)- and phosphatidylserine (PS)-dependent manner that was independent of SNARE concentrations. Munc13-4-SNARE interactions, under the conditions used, were minimal in the absence or presence of Ca(2+). However, Munc13-4 was able to bind and cluster liposomes harbouring PS in response to Ca(2+). Interestingly, Ca(2+)-dependent liposome binding/clustering and enhancement of proteoliposome fusion required both Munc13-4 C2 domains, but only the Ca(2+)-liganding aspartate residues of the C2B domain. Analytical ultracentrifugation (AUC) measurements indicated that, in solution, Munc13-4 was a monomeric prolate ellipsoid with dimensions consistent with a molecule that could bridge two fusing membranes. To address the potential role of Munc13-4 as a tethering protein in platelets, we examined mepacrine-stained, dense granule mobility and secretion in platelets from wild-type and Munc13-4 null (Unc13d(Jinx)) mice. In the absence of Munc13-4, dense granules were highly mobile in both resting and stimulated platelets, and stimulation-dependent granule release was absent. These observations suggest that dense granules are stably docked in resting platelets awaiting stimulation and that Munc13-4 plays a vesicle-stabilizing or tethering role in resting platelets and also in activated platelets in response to Ca(2+). In summary, we show that Munc13-4 conveys Ca(2+) sensitivity to platelet SNARE-mediated membrane fusion and reveal a potential mechanism by which Munc13-4 bridges and stabilizes apposing membranes destined for fusion.
    MeSH term(s) Animals ; Blood Platelets/physiology ; Blood Platelets/ultrastructure ; Calcium/metabolism ; Cell Fusion ; Exocytosis ; Humans ; Liposomes ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Mice, Knockout ; Mutation ; Phosphatidylserines/metabolism ; Rats ; SNARE Proteins/metabolism ; Secretory Vesicles/physiology ; Secretory Vesicles/ultrastructure
    Chemical Substances Liposomes ; Membrane Proteins ; Phosphatidylserines ; SNARE Proteins ; UNC13D protein, human ; Unc13d protein, mouse ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2016-03-01
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2969-5
    ISSN 1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
    ISSN (online) 1470-8728
    ISSN 0006-2936 ; 0306-3275 ; 0264-6021
    DOI 10.1042/BJ20151150
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  3. Article ; Online: Griscelli syndrome type 2 – A case report and clinical approach to silver blonde hair

    Sana Durrani / Michael Chicka / Bushra Afroze

    Egyptian Journal of Medical Human Genetics, Vol 17, Iss 2, Pp 229-

    2016  Volume 232

    Abstract: ... in the RAB27A gene was identified that showed a single base substitution (c.598C>T) predicted to cause premature ...

    Abstract Griscelli syndrome type 2 is a rare autosomal recessive disease caused by mutations in the RAB27A gene. It is characterized by pigmentary dilution of the skin and hair causing silvery gray hair, hemophagocytic lymphohistiocytosis and characteristic light microscopy findings in scalp hair shaft seen as large irregular clumps of pigment as opposed to the evenly distributed pigment along the hair shaft without any clumps. We describe a boy with classic features of Griscelli syndrome type 2 from Pakistan in whom a homozygous mutation in the RAB27A gene was identified that showed a single base substitution (c.598C>T) predicted to cause premature protein termination (p.Arg200∗). We also present a clinical approach to silver blonde hair differentiating between the Griscelli syndrome types 1, 2 and 3, Chediak Hegashi Syndrome and Elejalde Syndrome.
    Keywords Griscelli syndrome ; Silver blonde hair ; Bone marrow transplant ; Pakistan ; Medicine (General) ; R5-920 ; Genetics ; QH426-470
    Language English
    Publishing date 2016-04-01T00:00:00Z
    Publisher SpringerOpen
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Transient abnormal myelopoiesis of a newborn not associated with chromosome 21 abnormalities or GATA1 mutations.

    Nakashima, Megan O / Shetty, Shashirekha / Chicka, Michael / Flagg, Aron / Eng, Charis / Cotta, Claudiu V

    Pediatric blood & cancer

    2015  Volume 62, Issue 2, Page(s) 353–355

    Abstract: Transient abnormal myelopoiesis (TAM) is a disorder of Down syndrome newborns characterized by megakaryocytic blasts indistinguishable from acute myeloid leukemia (AML), which undergoes spontaneous remission. Acquired GATA1 mutations are present in ... ...

    Abstract Transient abnormal myelopoiesis (TAM) is a disorder of Down syndrome newborns characterized by megakaryocytic blasts indistinguishable from acute myeloid leukemia (AML), which undergoes spontaneous remission. Acquired GATA1 mutations are present in blasts of both TAM and the subsequent AML which sometimes develops. We present a unique case of a newborn with leukemic megakaryoblasts indistinguishable from those of TAM who had neither extra material from chromosome 21 in the germline or blasts, nor evidence of GATA1 mutations. These findings suggest there are other genetic abnormalities that can lead to TAM besides GATA1 mutation in the setting of trisomy 21. Pediatr Blood Cancer 2015;62:353-355. © 2014 Wiley Periodicals, Inc.
    MeSH term(s) Chromosomes, Human, Pair 21/genetics ; Down Syndrome/diagnosis ; Down Syndrome/genetics ; GATA1 Transcription Factor/genetics ; Humans ; Infant, Newborn ; Leukemoid Reaction/diagnosis ; Leukemoid Reaction/genetics ; Male ; Oligonucleotide Array Sequence Analysis
    Chemical Substances GATA1 Transcription Factor ; GATA1 protein, human
    Language English
    Publishing date 2015-02
    Publishing country United States
    Document type Case Reports ; Journal Article
    ZDB-ID 2131448-2
    ISSN 1545-5017 ; 1545-5009
    ISSN (online) 1545-5017
    ISSN 1545-5009
    DOI 10.1002/pbc.25226
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  5. Article: Analysis of the synaptotagmin family during reconstituted membrane fusion. Uncovering a class of inhibitory isoforms.

    Bhalla, Akhil / Chicka, Michael C / Chapman, Edwin R

    The Journal of biological chemistry

    2008  Volume 283, Issue 31, Page(s) 21799–21807

    Abstract: Ca(2+)-triggered exocytosis in neurons and neuroendocrine cells is regulated by the Ca(2+)-binding protein synaptotagmin (syt) I. Sixteen additional isoforms of syt have been identified, but little is known concerning their biochemical or functional ... ...

    Abstract Ca(2+)-triggered exocytosis in neurons and neuroendocrine cells is regulated by the Ca(2+)-binding protein synaptotagmin (syt) I. Sixteen additional isoforms of syt have been identified, but little is known concerning their biochemical or functional properties. Here, we assessed the abilities of fourteen syt isoforms to directly regulate SNARE (soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein receptor)-catalyzed membrane fusion. One group of isoforms stimulated neuronal SNARE-mediated fusion in response to Ca(2+), while another set inhibited SNARE catalyzed fusion in both the absence and presence of Ca(2+). Biochemical analysis revealed a strong correlation between the ability of syt isoforms to bind 1,2-dioleoyl phosphatidylserine (PS) and t-SNAREs in a Ca(2+)-promoted manner with their abilities to enhance fusion, further establishing PS and SNAREs as critical effectors for syt action. The ability of syt I to efficiently stimulate fusion was specific for certain SNARE pairs, suggesting that syts might contribute to the specificity of intracellular membrane fusion reactions. Finally, a subset of inhibitory syts down-regulated the ability of syt I to activate fusion, demonstrating that syt isoforms can modulate the function of each other.
    MeSH term(s) Animals ; Calcium/chemistry ; Gene Expression Regulation ; Humans ; Membrane Fusion ; Models, Biological ; Molecular Conformation ; Neurons/metabolism ; Plasmids/metabolism ; Protein Isoforms ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Rats ; SNARE Proteins/metabolism ; Synaptotagmins/chemistry ; Synaptotagmins/genetics ; Synaptotagmins/physiology
    Chemical Substances Protein Isoforms ; SNARE Proteins ; Synaptotagmins (134193-27-4) ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2008-05-28
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.M709628200
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  6. Article: Alternative splicing of the first intracellular loop of plasma membrane Ca2+-ATPase isoform 2 alters its membrane targeting.

    Chicka, Michael C / Strehler, Emanuel E

    The Journal of biological chemistry

    2003  Volume 278, Issue 20, Page(s) 18464–18470

    Abstract: Plasma membrane Ca(2+)-ATPases (PMCAs) are involved in local Ca(2+) signaling and in the spatial control of Ca(2+) extrusion, but how different PMCA isoforms are targeted to specific membrane domains is unknown. In polarized MDCK epithelial cells, a ... ...

    Abstract Plasma membrane Ca(2+)-ATPases (PMCAs) are involved in local Ca(2+) signaling and in the spatial control of Ca(2+) extrusion, but how different PMCA isoforms are targeted to specific membrane domains is unknown. In polarized MDCK epithelial cells, a green fluorescent protein-tagged PMCA4b construct was targeted to the basolateral membrane, whereas a green fluorescent protein-tagged PMCA2b construct was localized to both the apical and basolateral domain. The PDZ protein-binding COOH-terminal tail of PMCA2b was not responsible for its apical membrane localization, as a chimeric pump made of an NH(2)-terminal portion from PMCA4 and a COOH-terminal tail from PMCA2b was targeted to the basolateral domain. Deletion of the last six residues of the COOH terminus of either PMCA2b or PMCA4b did not alter their membrane targeting, suggesting that PDZ protein interactions are not essential for proper membrane localization of the pumps. Instead, we found that alternative splicing affecting the first cytosolic loop determined apical membrane targeting of PMCA2. Only the "w" form, which contains a 45-amino acid residue insertion, showed prominent apical membrane localization. By contrast, the x and z splice variants containing insertions of 14 and 0 residues, respectively, localized to the basolateral membrane. The w splice insert was the crucial determinant of apical PMCA2 localization, and this was independent of the splice configuration at the COOH-terminal end of the pump; both PMCA2w/b and PMCA2w/a showed prominent apical targeting, whereas PMCA2x/b, PMCA2z/b, and PMCA2z/a were confined to the basolateral membrane. These data report the first differential effect of alternative splicing within the first cytosolic loop of PMCA2 and help explain the selective enrichment of specific PMCA2 isoforms in specialized membrane compartments such as stereocilia of auditory hair cells.
    MeSH term(s) Alternative Splicing ; Animals ; COS Cells ; Calcium/metabolism ; Calcium-Transporting ATPases/chemistry ; Calcium-Transporting ATPases/metabolism ; Cation Transport Proteins ; Cell Membrane/enzymology ; Cell Membrane/metabolism ; Cytosol/metabolism ; Dogs ; Genetic Vectors ; Green Fluorescent Proteins ; Humans ; Immunoblotting ; Lipid Bilayers/metabolism ; Luminescent Proteins/metabolism ; Microscopy, Confocal ; Microscopy, Fluorescence ; Plasma Membrane Calcium-Transporting ATPases ; Protein Isoforms ; Protein Structure, Tertiary ; Recombinant Proteins/metabolism ; Transfection
    Chemical Substances Cation Transport Proteins ; Lipid Bilayers ; Luminescent Proteins ; Protein Isoforms ; Recombinant Proteins ; Green Fluorescent Proteins (147336-22-9) ; Plasma Membrane Calcium-Transporting ATPases (EC 3.6.3.8) ; ATP2B2 protein, human (EC 7.2.2.10) ; Calcium-Transporting ATPases (EC 7.2.2.10) ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2003-03-06
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.M301482200
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  7. Article ; Online: Gβγ directly modulates vesicle fusion by competing with synaptotagmin for binding to neuronal SNARE proteins embedded in membranes.

    Zurawski, Zack / Page, Brian / Chicka, Michael C / Brindley, Rebecca L / Wells, Christopher A / Preininger, Anita M / Hyde, Karren / Gilbert, James A / Cruz-Rodriguez, Osvaldo / Currie, Kevin P M / Chapman, Edwin R / Alford, Simon / Hamm, Heidi E

    The Journal of biological chemistry

    2017  Volume 292, Issue 29, Page(s) 12165–12177

    Abstract: ... ...

    Abstract G
    MeSH term(s) Animals ; Binding, Competitive ; Calcium Signaling ; Cattle ; Cell Line ; GTP-Binding Protein beta Subunits/chemistry ; GTP-Binding Protein beta Subunits/genetics ; GTP-Binding Protein beta Subunits/metabolism ; GTP-Binding Protein gamma Subunits/chemistry ; GTP-Binding Protein gamma Subunits/genetics ; GTP-Binding Protein gamma Subunits/metabolism ; Humans ; Lipid Bilayers ; Liposomes ; Membrane Fusion ; Models, Molecular ; Mutation ; Nerve Tissue Proteins/chemistry ; Nerve Tissue Proteins/metabolism ; Peptide Fragments/chemistry ; Peptide Fragments/genetics ; Peptide Fragments/metabolism ; Protein Conformation ; Protein Interaction Domains and Motifs ; Protein Multimerization ; Rats ; Recombinant Fusion Proteins/chemistry ; Recombinant Fusion Proteins/metabolism ; Recombinant Proteins/chemistry ; Recombinant Proteins/metabolism ; Synaptosomal-Associated Protein 25/chemistry ; Synaptosomal-Associated Protein 25/metabolism ; Synaptotagmin I/chemistry ; Synaptotagmin I/genetics ; Synaptotagmin I/metabolism ; Syntaxin 1/chemistry ; Syntaxin 1/metabolism
    Chemical Substances GTP-Binding Protein beta Subunits ; GTP-Binding Protein gamma Subunits ; Lipid Bilayers ; Liposomes ; Nerve Tissue Proteins ; Peptide Fragments ; Recombinant Fusion Proteins ; Recombinant Proteins ; Snap25 protein, rat ; Stx1a protein, rat ; Synaptosomal-Associated Protein 25 ; Synaptotagmin I ; Syntaxin 1 ; Syt1 protein, rat
    Language English
    Publishing date 2017-05-17
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.M116.773523
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  8. Article ; Online: Synaptotagmin arrests the SNARE complex before triggering fast, efficient membrane fusion in response to Ca2+.

    Chicka, Michael C / Hui, Enfu / Liu, Huisheng / Chapman, Edwin R

    Nature structural & molecular biology

    2008  Volume 15, Issue 8, Page(s) 827–835

    Abstract: Neuronal communication is mediated by Ca(2+)-triggered fusion of transmitter-filled synaptic vesicles with the presynaptic plasma membrane. Synaptotagmin I functions as a Ca(2+) sensor that regulates exocytosis, whereas soluble N-ethylmaleimide-sensitive ...

    Abstract Neuronal communication is mediated by Ca(2+)-triggered fusion of transmitter-filled synaptic vesicles with the presynaptic plasma membrane. Synaptotagmin I functions as a Ca(2+) sensor that regulates exocytosis, whereas soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) receptor (SNARE) proteins in the vesicle and target membrane assemble into complexes that directly catalyze bilayer fusion. Here we report that, before the Ca(2+) trigger, synaptotagmin interacts with SNARE proteins in the target membrane to halt SNARE complex assembly at a step after donor vesicles attach, or dock, to target membranes. This results in fusion complexes that, when subsequently triggered by Ca(2+), drive rapid, highly efficient lipid mixing. Ca(2+)-independent interactions with SNAREs also predispose synaptotagmin to selectively penetrate the target membrane in response to Ca(2+); we demonstrate that Ca(2+)-synaptotagmin must insert into the target membrane to accelerate SNARE-catalyzed fusion. These findings demonstrate that Ca(2+) converts synaptotagmin from a clamp to a trigger for exocytosis.
    MeSH term(s) Animals ; Calcium/metabolism ; Catalysis ; Cell Membrane/metabolism ; Electrophysiology ; Exocytosis ; Hippocampus/metabolism ; Lipids/chemistry ; Mice ; Mice, Knockout ; Models, Biological ; Plasmids/metabolism ; Rats ; SNARE Proteins/metabolism ; Synaptotagmins/metabolism ; Synaptotagmins/physiology
    Chemical Substances Lipids ; SNARE Proteins ; Synaptotagmins (134193-27-4) ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2008-07-11
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2126708-X
    ISSN 1545-9985 ; 1545-9993
    ISSN (online) 1545-9985
    ISSN 1545-9993
    DOI 10.1038/nsmb.1463
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  9. Article ; Online: IκB kinase phosphorylation of SNAP-23 controls platelet secretion.

    Karim, Zubair A / Zhang, Jinchao / Banerjee, Meenakshi / Chicka, Michael C / Al Hawas, Rania / Hamilton, Tara R / Roche, Paul A / Whiteheart, Sidney W

    Blood

    2013  Volume 121, Issue 22, Page(s) 4567–4574

    Abstract: ... phospholipase C, [Ca(2+)]i, protein kinase C) and requires IκB kinase (IKK)-β. Other elements of the nuclear ...

    Abstract Platelet secretion plays a key role in thrombosis, thus the platelet secretory machinery offers a unique target to modulate hemostasis. We report the regulation of platelet secretion via phosphorylation of SNAP-23 at Ser95. Phosphorylation of this t-soluble N-ethylmaleimide sensitive factor attachment protein receptor (SNARE) occurs upon activation of known elements of the platelet signaling cascades (ie, phospholipase C, [Ca(2+)]i, protein kinase C) and requires IκB kinase (IKK)-β. Other elements of the nuclear factor κB/IκB cascade (ie, IKK-α,-β,-γ/NEMO and CARMA/MALT1/Bcl10 complex) are present in anucleate platelets and IκB is phosphorylated upon activation, suggesting that this pathway is active in platelets and implying a nongenomic role for IKK. Inhibition of IKK-β, either pharmacologically (with BMS-345541, BAY11-7082, or TPCA-1) or by genetic manipulation (platelet factor 4 Cre:IKK-β(flox/flox)), blocked SNAP-23 phosphorylation, platelet secretion, and SNARE complex formation; but, had no effect on platelet morphology or other metrics of platelet activation. Consistently, SNAP-23 phosphorylation enhanced membrane fusion of SNARE-containing proteoliposomes. In vivo studies with IKK inhibitors or platelet-specific IKK-β knockout mice showed that blocking IKK-β activity significantly prolonged tail bleeding times, suggesting that currently available IKK inhibitors may affect hemostasis.
    MeSH term(s) Animals ; Blood Platelets/metabolism ; Cytoplasmic Granules/metabolism ; Enzyme Activation/physiology ; Hemostasis/physiology ; I-kappa B Kinase/genetics ; I-kappa B Kinase/metabolism ; Membrane Fusion/physiology ; Mice ; Mice, Knockout ; Phosphorylation/physiology ; Platelet Activation/physiology ; Qb-SNARE Proteins/metabolism ; Qc-SNARE Proteins/metabolism ; SNARE Proteins/metabolism ; Signal Transduction/physiology
    Chemical Substances Qb-SNARE Proteins ; Qc-SNARE Proteins ; SNARE Proteins ; Snap23 protein, mouse ; I-kappa B Kinase (EC 2.7.11.10)
    Language English
    Publishing date 2013-04-23
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 80069-7
    ISSN 1528-0020 ; 0006-4971
    ISSN (online) 1528-0020
    ISSN 0006-4971
    DOI 10.1182/blood-2012-11-470468
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  10. Article: Ca(2+)-synaptotagmin directly regulates t-SNARE function during reconstituted membrane fusion.

    Bhalla, Akhil / Chicka, Michael C / Tucker, Ward C / Chapman, Edwin R

    Nature structural & molecular biology

    2006  Volume 13, Issue 4, Page(s) 323–330

    Abstract: In nerve terminals, exocytosis is mediated by SNARE proteins and regulated by Ca(2+) and synaptotagmin-1 (syt). Ca(2+) promotes the interaction of syt with anionic phospholipids and the target membrane SNAREs (t-SNAREs) SNAP-25 and syntaxin. Here, we ... ...

    Abstract In nerve terminals, exocytosis is mediated by SNARE proteins and regulated by Ca(2+) and synaptotagmin-1 (syt). Ca(2+) promotes the interaction of syt with anionic phospholipids and the target membrane SNAREs (t-SNAREs) SNAP-25 and syntaxin. Here, we have used a defined reconstituted fusion assay to determine directly whether syt-t-SNARE interactions couple Ca(2+) to membrane fusion by comparing the effects of Ca(2+)-syt on neuronal (SNAP-25, syntaxin and synaptobrevin) and yeast (Sso1p, Sec9c and Snc2p) SNAREs. Ca(2+)-syt aggregated neuronal and yeast SNARE liposomes to similar extents via interactions with anionic phospholipids. However, Ca(2+)-syt was able to bind and stimulate fusion mediated by only neuronal SNAREs and had no effect on yeast SNAREs. Thus, Ca(2+)-syt regulates fusion through direct interactions with t-SNAREs and not solely through aggregation of vesicles. Ca(2+)-syt drove assembly of SNAP-25 onto membrane-embedded syntaxin, providing direct evidence that Ca(2+)-syt alters t-SNARE structure.
    MeSH term(s) Animals ; Calcium/metabolism ; Exocytosis ; Fungal Proteins/genetics ; Fungal Proteins/metabolism ; In Vitro Techniques ; Liposomes ; Membrane Fusion/physiology ; Models, Biological ; Mutagenesis, Site-Directed ; Nerve Endings/metabolism ; Rats ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; SNARE Proteins/genetics ; SNARE Proteins/metabolism ; Synaptosomal-Associated Protein 25/genetics ; Synaptosomal-Associated Protein 25/metabolism ; Synaptotagmin I/genetics ; Synaptotagmin I/metabolism
    Chemical Substances Fungal Proteins ; Liposomes ; Recombinant Proteins ; SNARE Proteins ; Synaptosomal-Associated Protein 25 ; Synaptotagmin I ; Syt1 protein, rat ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2006-04
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2126708-X
    ISSN 1545-9985 ; 1545-9993
    ISSN (online) 1545-9985
    ISSN 1545-9993
    DOI 10.1038/nsmb1076
    Database MEDical Literature Analysis and Retrieval System OnLINE

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