17 results on '"Posor, York"'
Search Results
2. A Golgi-associated lipid kinase controls peripheral nerve myelination
- Author
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Posor, York and Haucke, Volker
- Published
- 2020
3. PI3K isoforms in cell signalling and vesicle trafficking
- Author
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Bilanges, Benoit, Posor, York, and Vanhaesebroeck, Bart
- Published
- 2019
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4. A three-way organelle junction controls PI(4)P metabolism and mitochondrial division.
- Author
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Posor, York and Haucke, Volker
- Subjects
- *
CELL membranes , *ORGANELLES , *MITOCHONDRIA , *FACILITATED communication , *METABOLISM - Abstract
Membrane contact sites (MCS) facilitate communication between organelles. Casler et al. (https://doi.org/10.1083/jcb.202308144) show that tripartite MCS between mitochondria, the endoplasmic reticulum (ER), and the plasma membrane (PM) regulate mitochondrial division and the distribution of phosphatidylinositol 4-phosphate [PI(4)P] on the PM. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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5. Crystal structure of the dynamin tetramer
- Author
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Reubold, Thomas F., Faelber, Katja, Plattner, Nuria, Posor, York, Ketel, Katharina, Curth, Ute, Schlegel, Jeanette, Anand, Roopsee, Manstein, Dietmar J., Noe, Frank, Haucke, Volker, Daumke, Oliver, and Eschenburg, Susanne
- Subjects
Molecular dynamics -- Analysis ,Crystals -- Structure ,Oligomers -- Structure -- Models ,Markov processes -- Usage ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
The mechanochemical protein dynamin is the prototype of the dynamin superfamily of large GTPases, which shape and remodel membranes in diverse cellular processes (1). Dynamin forms predominantly tetramers in the cytosol, which oligomerize at the neck of clathrin-coated vesicles to mediate constriction and subsequent scission of the membrane (1). Previous studies have described the architecture of dynamin dimers (2,3), but the molecular determinants for dynamin assembly and its regulation have remained unclear. Here we present the crystal structure of the human dynamin tetramer in the nucleotide-free state. Combining structural data with mutational studies, oligomerization measurements and Markov state models of molecular dynamics simulations, we suggest a mechanism by which oligomerization of dynamin is linked to the release of intramolecular autoinhibitory interactions. We elucidate how mutations that interfere with tetramer formation and autoinhibition can lead to the congenital muscle disorders Charcot-Marie-Tooth neuropathy (4) and centronuclear myopathy (5), respectively. Notably, the bent shape of the tetramer explains how dynamin assembles into a right-handed helical oligomer of defined diameter, which has direct implications for its function in membrane constriction., The three highly conserved vertebrate isoforms of dynamin contain five distinct domains (Extended Data Fig. 1a): an N-terminal GTPase (G) domain mediating nucleotide binding and hydrolysis, a bundle signalling element [...]
- Published
- 2015
6. Antagonistic control of active surface integrins by myotubularin and phosphatidylinositol 3-kinase C2β in a myotubular myopathy model.
- Author
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Samsó, Paula, Koch, Philipp A., Posor, York, Wen-Ting Lo, Belabed, Hassane, Nazare, Marc, Laporte, Jocelyn, and Haucke, Volker
- Subjects
PHOSPHATIDYLINOSITOL 3-kinases ,FOCAL adhesions ,INTEGRINS ,MUSCLE diseases ,GENE silencing ,GENETIC counseling ,FIREPROOFING agents - Abstract
X-linked centronuclear myopathy (XLCNM) is a severe human disease without existing therapies caused by mutations in the phosphoinositide 3-phosphatase MTM1. Loss of MTM1 function is associated with muscle fiber defects characterized by impaired localization of β-integrins and other components of focal adhesions. Here we show that defective focal adhesions and reduced active β-integrin surface levels in a cellular model of XLCNM are rescued by loss of phosphatidylinositiol 3-kinase C2β (PI3KC2β) function. Inactivation of the Mtm1 gene impaired myoblast differentiation into myotubes and resulted in reduced surface levels of active β1-integrins as well as corresponding defects in focal adhesions. These phenotypes were rescued by concomitant genetic loss of Pik3c2b or pharmacological inhibition of PI3KC2β activity. We further demonstrate that a hitherto unknown role of PI3KC2β in the endocytic trafficking of active β1-integrins rather than rescue of phosphatidylinositol 3-phosphate levels underlies the ability of Pik3c2b to act as a genetic modifier of cellular XLCNM phenotypes. Our findings reveal a crucial antagonistic function of MTM1 and PI3KC2β in the control of active β-integrin surface levels, thereby providing a molecular mechanism for the adhesion and myofiber defects observed in XLCNM. They further suggest specific pharmacological inhibition of PI3KC2β catalysis as a viable treatment option for XLCNM patients. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
7. Spatiotemporal control of endocytosis by phosphatidylinositol-3,4-bisphosphate
- Author
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Posor, York, Eichhorn-Gruenig, Marielle, Puchkov, Dmytro, Schoneberg, Johannes, Ullrich, Alexander, Lampe, Andre, Muller, Rainer, Zarbakhsh, Sirus, Gulluni, Federico, Hirsch, Emilio, Krauss, Michael, Schultz, Carsten, Schmoranzer, Jan, Noe, Frank, and Haucke, Volker
- Subjects
Phosphoinositides -- Physiological aspects ,Endocytosis -- Research ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Phosphoinositides serve crucial roles in cell physiology, ranging from cell signalling to membrane traffic (1,2). Among the seven eukaryotic phosphoinositides the best studied species is phosphatidylinositol-4,5-bisphosphate (PI(4,5)[P.sub.2]), which is concentrated at the plasma membrane where, among other functions, it is required for the nucleation of endocytic clathrin-coated pits (3-6). No phosphatidylinositol other than PI(4,5)[P.sub.2] has been implicated in clathrin-mediated endocytosis, whereas the subsequent endosomal stages of the endocytic pathway are dominated by phosphatidylinositol 3-phosphates(PI(3)P) (7). How phosphatidylinositol conversion from PI(4,5)[P.sub.2]-positive endocytic intermediates to PI(3)P-containing endosomes is achieved is unclear. Here we show that formation of phosphatidylinositol-3,4-bisphosphate (PI(3,4)[P.sub.2]) by class II phosphatidylinositol-3-kinase C2α (PI(3)K C2α) spatiotemporally controls clathrin-mediated endocytosis. Depletion of PI(3,4)[P.sub.2] or PI(3)K C2α impairs the maturation of late-stage clathrin-coated pits before fission. Timed formation of PI(3,4)[P.sub.2] by PI(3)K C2α is required for selective enrichment of the BAR domain protein SNX9 at late-stage endocytic intermediates. These findings provide a mechanistic framework for the role of PI(3,4)[P.sub.2] in endocytosis and unravel a novel discrete function of PI(3,4)[P.sub.2] in a central cell physiological process., PI(4,5)[P.sub.2] generation by phosphatidylinositol phosphate-5-kinases (phosphatidylinositol-5-kinases) is required for recruitment of early PI(4,5)[P.sub.2]-associated coat components to mediate clathrin-coated pit (CCP) nucleation in clathrin-mediated endocytosis (CME) (1,5). Although phosphatidylinositol-5-kinases can associate [...]
- Published
- 2013
8. Crystal structure of nucleotide-free dynamin
- Author
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Faelber, Katja, Posor, York, Gao, Song, Held, Martin, Roske, Yvette, Schulze, Dennis, Haucke, Volker, Noe, Frank, and Daumke, Oliver
- Subjects
Synaptic vesicles -- Research -- Physiological aspects ,Cellular signal transduction -- Research ,Guanosine triphosphatase -- Physiological aspects -- Research ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Dynamin is a mechanochemical GTPase that oligomerizes around the neck of clathrin-coated pits and catalyses vesicle scission in a GTP-hydrolysis-dependent manner. The molecular details of oligomerization and the mechanism of the mechanochemical coupling are currently unknown. Here we present the crystal structure of human dynamin 1 in the nucleotide-free state with a four-domain architecture comprising the GTPase domain, the bundle signalling element, the stalk and the pleckstrin homology domain. Dynamin 1 oligomerized in the crystals via the stalks, which assemble in a criss-cross fashion. The stalks further interact via conserved surfaces with the pleckstrin homology domain and the bundle signalling element of the neighbouring dynamin molecule. This intricate domain interaction rationalizes a number of disease-related mutations in dynamin 2 and suggests a structural model for the mechanochemical coupling that reconciles previous models of dynamin function., Dynamin, the founding member of the dynamin superfamily, is a 100-kDa mechanochemical enzyme (Fig. 1a) involved in the scission of clathrin-coated vesicles from the plasma membrane (1). The brain-specific isoform [...]
- Published
- 2011
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9. The progressive ankylosis protein ANK facilitates clathrin- and adaptor-mediated membrane traffic at the trans-Golgi network-to-endosome interface.
- Author
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Seifert, Wenke, Posor, York, Schu, Peter, Stenbeck, Gudrun, Mundlos, Stefan, Klaassen, Sabine, Nürnberg, Peter, Haucke, Volker, Kornak, Uwe, and Kühnisch, Jirko
- Published
- 2016
- Full Text
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10. Inactivation of the Class II PI3K-C2β Potentiates Insulin Signaling and Sensitivity.
- Author
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Alliouachene, Samira, Bilanges, Benoit, Chicanne, Gaëtan, Anderson, Karen E., Pearce, Wayne, Ali, Khaled, Valet, Colin, Posor, York, Low, Pei Ching, Chaussade, Claire, Scudamore, Cheryl L., Salamon, Rachel S., Backer, Jonathan M., Stephens, Len, Hawkins, Phill T., Payrastre, Bernard, and Vanhaesebroeck, Bart
- Abstract
Summary In contrast to the class I phosphoinositide 3-kinases (PI3Ks), the organismal roles of the kinase activity of the class II PI3Ks are less clear. Here, we report that class II PI3K-C2β kinase-dead mice are viable and healthy but display an unanticipated enhanced insulin sensitivity and glucose tolerance, as well as protection against high-fat-diet-induced liver steatosis. Despite having a broad tissue distribution, systemic PI3K-C2β inhibition selectively enhances insulin signaling only in metabolic tissues. In a primary hepatocyte model, basal PI3P lipid levels are reduced by 60% upon PI3K-C2β inhibition. This results in an expansion of the very early APPL1-positive endosomal compartment and altered insulin receptor trafficking, correlating with an amplification of insulin-induced, class I PI3K-dependent Akt signaling, without impacting MAPK activity. These data reveal PI3K-C2β as a critical regulator of endosomal trafficking, specifically in insulin signaling, and identify PI3K-C2β as a potential drug target for insulin sensitization. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
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11. Phosphoinositides in endocytosis.
- Author
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Posor, York, Eichhorn-Grünig, Marielle, and Haucke, Volker
- Subjects
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PHOSPHOINOSITIDES , *PHOSPHORIC acid , *PHOSPHOLIPIDS , *ENDOCYTOSIS , *CELL physiology - Abstract
The internalization and subsequent endosomal trafficking of proteins and membrane along the endocytic pathway is a fundamental cellular process. Over the last two decades, this pathway has emerged to be subject to extensive regulation by phosphoinositides (PIs), phosphorylated derivatives of the minor membrane phospholipid phosphatidylinositol. Clathrin-mediated endocytosis (CME) is the endocytic mechanism characterized in most detail. It now represents a prime example of a process spatiotemporally organized by the interplay of PI metabolizing enzymes. The most abundant PI, phosphatidylinositol-4,5-bisphosphate [PI(4,5)P 2 ], serves as a denominator of plasma membrane identity and together with cargo proteins is instrumental for the initiation of clathrin-coated pit (CCP) formation. During later stages of the process, the generation of phosphatidylinositol-3,4-bisphosphate [PI(3,4)P 2 ] and the dephosphorylation of PI(4,5)P 2 regulate CCP maturation and vesicle uncoating. Here we provide an overview of the mechanisms by which PIs are made and consumed to regulate CME and other endocytic pathways and how conversion of PIs en route to endosomes may be accomplished. Mutations in PI converting enzymes are linked to multiple diseases ranging from mental retardation and neurodegeneration, to inherited muscle and kidney disorders suggesting that the tight control of PI levels along the endocytic pathway plays a critical role in cell physiology. This article is part of a Special Issue entitled Phosphoinositides. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
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12. Local synthesis of the phosphatidylinositol-3,4-bisphosphate lipid drives focal adhesion turnover.
- Author
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Posor, York, Kampyli, Charis, Bilanges, Benoit, Ganguli, Sushila, Koch, Philipp A., Wallroth, Alexander, Morelli, Daniele, Jenkins, Michalina, Alliouachene, Samira, Deltcheva, Elitza, Baum, Buzz, Haucke, Volker, and Vanhaesebroeck, Bart
- Subjects
- *
CELL-matrix adhesions , *ADHESION , *FOCAL adhesions , *LIPID synthesis , *MEMBRANE lipids , *PROTEIN kinases , *COLLECTIVE behavior , *FOCAL adhesion kinase - Abstract
Focal adhesions are multifunctional organelles that couple cell-matrix adhesion to cytoskeletal force transmission and signaling and to steer cell migration and collective cell behavior. Whereas proteomic changes at focal adhesions are well understood, little is known about signaling lipids in focal adhesion dynamics. Through the characterization of cells from mice with a kinase-inactivating point mutation in the class II PI3K-C2β, we find that generation of the phosphatidylinositol-3,4-bisphosphate (PtdIns(3,4)P 2) membrane lipid promotes focal adhesion disassembly in response to changing environmental conditions. We show that reduced growth factor signaling sensed by protein kinase N, an mTORC2 target and effector of RhoA, synergizes with the adhesion disassembly factor DEPDC1B to induce local synthesis of PtdIns(3,4)P 2 by PI3K-C2β. PtdIns(3,4)P 2 then promotes turnover of RhoA-dependent stress fibers by recruiting the PtdIns(3,4)P 2 -dependent RhoA-GTPase-activating protein ARAP3. Our findings uncover a pathway by which cessation of growth factor signaling facilitates cell-matrix adhesion disassembly via a phosphoinositide lipid switch. [Display omitted] • PtdIns(3,4)P 2 produced by PI3K-C2β promote focal adhesion disassembly • PI3K-C2β recruitment to adhesions is regulated via phosphorylation by PKN2 • Local PtdIns(3,4)P 2 formation inactivates RhoA through recruitment of the ARAP3 GAP Remodeling of cell-matrix adhesions is crucial for development and tissue homeostasis. Posor, Kampyli et al. show that synthesis of the phosphatidylinositol-3,4-bisphosphate (PtdIns(3,4)P 2) membrane lipid promotes disassembly of focal adhesions by inactivating the RhoA small GTPase. This identifies a pathway that links cessation of growth factor signaling to adhesion disassembly through a membrane lipid switch. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
13. Lipid-mediated PX-BAR domain recruitment couples local membrane constriction to endocytic vesicle fission.
- Author
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Schöneberg, Johannes, Lehmann, Martin, Ullrich, Alexander, Posor, York, Lo, Wen-Ting, Lichtner, Gregor, Schmoranzer, Jan, Haucke, Volker, and Noé, Frank
- Abstract
Clathrin-mediated endocytosis (CME) involves membrane-associated scaffolds of the bin-amphiphysin-rvs (BAR) domain protein family as well as the GTPase dynamin, and is accompanied and perhaps triggered by changes in local lipid composition. How protein recruitment, scaffold assembly and membrane deformation is spatiotemporally controlled and coupled to fission is poorly understood. We show by computational modelling and super-resolution imaging that phosphatidylinositol 3,4-bisphosphate [PI(3,4)P
2 ] synthesis within the clathrin-coated area of endocytic intermediates triggers selective recruitment of the PX-BAR domain protein SNX9, as a result of complex interactions of endocytic proteins competing for phospholipids. The specific architecture induces positioning of SNX9 at the invagination neck where its self-assembly regulates membrane constriction, thereby providing a template for dynamin fission. These data explain how lipid conversion at endocytic pits couples local membrane constriction to fission. Our work demonstrates how computational modelling and super-resolution imaging can be combined to unravel function and mechanisms of complex cellular processes. [ABSTRACT FROM AUTHOR]- Published
- 2017
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14. PI4K2β/AP-1-Based TGN-Endosomal Sorting Regulates Wnt Signaling.
- Author
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Wieffer, Marnix, Cibrián?Uhalte, Elena, Posor, York, Otten, Cécile, Branz, Katharina, Schütz, Irene, Mössinger, Julia, Schu, Peter, Abdelilah-Seyfried, Salim, Krauß, Michael, and Haucke, Volker
- Subjects
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WNT proteins , *CELLULAR signal transduction , *CELL physiology , *CELL growth , *ENDOSOMES , *GOLGI apparatus , *ADAPTOR proteins - Abstract
Summary: Endosomal membrane traffic serves crucial roles in cell physiology, signaling, and development [1–4]. Sorting between endosomes and the trans-Golgi network (TGN) is regulated among other factors by the adaptor AP-1, an essential component of multicellular organisms [5]. Membrane recruitment of AP-1 requires phosphatidylinositol 4-phosphate [PI(4)P], though the precise mechanisms and PI4 kinase isozyme (or isozymes) involved in generation of this PI(4)P pool remain unclear [6, 7]. The Wnt pathway is a major developmental signaling cascade and depends on endosomal sorting in Wnt-sending cells [8–10]. Whether TGN/endosomal sorting modulates signaling downstream of Frizzled (Fz) receptors in Wnt-receiving cells is unknown. Here, we identify PI4-kinase type 2β (PI4K2β) as a regulator of TGN/endosomal sorting and Wnt signaling. PI4K2β and AP-1 interact directly and are required for efficient sorting between endosomes and the TGN. Zebrafish embryos depleted of PI4K2β or AP-1 lack pectoral fins due to defective Wnt signaling. Rescue experiments demonstrate requirements for PI4K2β-AP-1 complex formation and PI4K2β-mediated PI(4)P synthesis. Furthermore, PI4K2β binds to the Fz-associated component Dishevelled (Dvl) and regulates endosomal recycling of Fz receptors and Wnt target gene expression. These data reveal an evolutionarily conserved role for PI4K2β and AP-1 in coupling phosphoinositide metabolism to AP-1-mediated sorting and Wnt signaling. [Copyright &y& Elsevier]
- Published
- 2013
- Full Text
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15. PI3K Class II α Controls Spatially Restricted Endosomal PtdIns3P and Rab11 Activation to Promote Primary Cilium Function.
- Author
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Franco, Irene, Gulluni, Federico, Campa, Carlo?C., Costa, Carlotta, Margaria, Jean?Piero, Ciraolo, Elisa, Martini, Miriam, Monteyne, Daniel, De?Luca, Elisa, Germena, Giulia, Posor, York, Maffucci, Tania, Marengo, Stefano, Haucke, Volker, Falasca, Marco, Perez-Morga, David, Boletta, Alessandra, Merlo, Giorgio?R., and Hirsch, Emilio
- Subjects
- *
PHOSPHATIDYLINOSITOL 3-kinases , *ENDOCYTOSIS , *ORGANELLES , *ENDOSOMES , *ORGAN trafficking , *CELLULAR signal transduction - Abstract
Summary: Multiple phosphatidylinositol (PtdIns) 3-kinases (PI3Ks) can produce PtdIns3P to control endocytic trafficking, but whether enzyme specialization occurs in defined subcellular locations is unclear. Here, we report that PI3K-C2α is enriched in the pericentriolar recycling endocytic compartment (PRE) at the base of the primary cilium, where it regulates production of a specific pool of PtdIns3P. Loss of PI3K-C2α-derived PtdIns3P leads to mislocalization of PRE markers such as TfR and Rab11, reduces Rab11 activation, and blocks accumulation of Rab8 at the primary cilium. These changes in turn cause defects in primary cilium elongation, Smo ciliary translocation, and Sonic Hedgehog (Shh) signaling and ultimately impair embryonic development. Selective reconstitution of PtdIns3P levels in cells lacking PI3K-C2α rescues Rab11 activation, primary cilium length, and Shh pathway induction. Thus, PI3K-C2α regulates the formation of a PtdIns3P pool at the PRE required for Rab11 and Shh pathway activation. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
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16. Structural Insights into Dynamin-Mediated Membrane Fission
- Author
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Faelber, Katja, Held, Martin, Gao, Song, Posor, York, Haucke, Volker, Noé, Frank, and Daumke, Oliver
- Subjects
- *
PROTEIN structure , *DYNAMIN (Genetics) , *MEMBRANE proteins , *MECHANICAL chemistry , *REARRANGEMENTS (Chemistry) , *OLIGOMERS - Abstract
Dynamin is a multidomain mechanochemical guanine triphosphatase that catalyzes membrane scission, most notably of clathrin-coated endocytic vesicles. A number of recent publications have provided structural and mechanistic insights into the formation of helical dynamin filaments assembled by dynamic interactions of multiple domains within dynamin. As a prerequisite for membrane scission, this oligomer undergoes nucleotide-triggered large scale dynamic rearrangements. Here, we review these structural findings and discuss how the architecture of dynamin is poised for the assembly into right-handed helical filaments. Based on these data, we propose a structure-based model for dynamin-mediated scission of membranes. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
17. Oligomerization of dynamin superfamily proteins in health and disease.
- Author
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Faelber K, Gao S, Held M, Posor Y, Haucke V, Noé F, and Daumke O
- Subjects
- Animals, Dynamins chemistry, Dynamins genetics, Humans, Models, Molecular, Mutation genetics, Protein Multimerization, Disease genetics, Dynamins metabolism, Health
- Abstract
Proteins of the dynamin superfamily are mechanochemical GTPases, which mediate nucleotide-dependent membrane remodeling events. The founding member dynamin is recruited to the neck of clathrin-coated endocytic vesicles where it oligomerizes into helical filaments. Nucleotide-hydrolysis-induced conformational changes in the oligomer catalyze scission of the vesicle neck. Here, we review recent insights into structure, function, and oligomerization of dynamin superfamily proteins and their roles in human diseases. We describe in detail the molecular mechanisms how dynamin oligomerizes at membranes and introduce a model how oligomerization is linked to membrane fission. Finally, we discuss molecular mechanisms how mutations in dynamin could lead to the congenital diseases, Centronuclear Myopathy and Charcot-Marie Tooth disease., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
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