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13 Dysferlin and the ferlin family; an ancient family of calcium-sensitive vesicle fusion proteins Sandra Cooper 1, 2 , Frances Evesson 1, 2 , Angela Lek 1, 2 , Monkol Lek 1, 2 , Rachel Peat 1 , Kathryn North 1, 2 . Institute for Neuroscience and Muscle Research, Children’s Hospital at Westmead, Sydney, Australia. 1 , Discipline of Paediatrics and Child Health, University of Sydney, Sydney, Australia. 2 Abstract: The ferlin gene family are tail-anchored proteins possessing a rare and identifying feature of multiple tandem C2 domains and a C-terminal transmembrane domain. Ferlins bear structural homology to the synaptotagmin family of vesicle fusion proteins, and mutations in two mammalian ferlins are linked to human diseases characterised by abnormal vesicle fusion. Mutations in dysferlin underlie an autosomal recessive form of muscular dystrophy due to defective vesicle-mediated membrane resealing, and, mutations in otoferlin cause an autosomal recessive form of non-syndromic deafness caused by defective synaptic vesicle fusion within the cochlear. We show that ferlin proteins have ancient origins in eukaryotic biology, with ancestral ferlins identified in simple unicellular eukaryotes that lack synaptotagmin-like homologues of plants and higher order eukaryotes. We are trying to understand the cellular role of dysferlin, and how it regulates calcium-activated vesicle-mediated membrane resealing. Our studies of dysferlin cell biology reveal a short-lived and transitory transmembrane protein, with a propensity for rapid endocytosis when mutated. Accelerated dysferlin endocytosis, and subsequent endosomal-driven degradation, provides a new explanation as to why some patients with single amino-acid mutations, show dysferlin deficiency. Our recent studies have shown that dysferlin regulates the expression of syntaxin-4, and, that dysferlin and syntaxin-4 similarly transit a common endosomal pathway in skeletal muscle cells. Despite its well characterised role in regulated exocytosis, there are significant gaps in current understanding of endosomal trafficking of syntaxin-4. Dysferlin provides a novel marker of syntaxin-4 endosomal transit in muscle cells, perhaps also relevant to dysferlin’s role in the calcium-activated exocytosis of membrane resealing.
14 Mechanistic details of sorting nexin dependent retrograde endosome-to-Golgi transport Chris Danson 1 , Ian McGough 1 , Jan van Weering 1 , Peter Cullen 1 . Bristol University 1 Abstract: Compared with our understanding of the molecular details that underlie the processes of endocytosis, how cells regulate retrograde protein and lipid movement between endosomes and the Golgi apparatus is poorly described. One evolutionarily conserved complexes involved in such retrograde transport is the retromer. Mammalian retromer is composed of two subcomplexes: a cargo-selective VPS26-VPS29-VPS35 trimer, this binds to cargo including the CI- MPR, and an endosomal bound coat comprising specific heterodimeric combinations of the sorting nexins (SNXs) SNX1/SNX2 and SNX5/SNX6. Through the presence of a BAR (Bin/amphiphysin/Rvs) domain, these SNX-BAR proteins drive and stabilize the formation of membrane tubules thereby coupling cargo sorting to the process of donor membrane deformation. In recently published work, we have described how this canonical retromer coat associates with the minus-end direct microtubule motor dynein in order to aid the efficiency of carrier scission and allow for long-range carrier movement. In addition, we have established a role for the retromer coat in the recognition of incoming carriers at the Golgi complex. Here we describe the molecular details of a SNX8-dependent tubular-based endosome-to-Golgi retrograde transport pathway that regulates sorting of a specific set of SNARE proteins. Using a combination of in vitro liposome assays, yeast two-hybrid analysis, proteomics and biochemistry, advanced light and electron microscopy coupled with RNAi-studies in mammalian cells, we establish how this pathway functions independently of the retromer, define the mechanistic details through which the BAR domain-containing SNX8 and the canonical retromer SNX-BARs reside on, and drive the formation of distinct endosomal tubules, and elucidate the molecular basis through which recognition of the SNAREs are achieved.
Page 1 and 2: October 28 - October 31, 2010 Bioch
Page 3 and 4: Symposium Agenda Thursday, October
Page 5 and 6: 12:10 p.m. - 4:00 p.m. Lunch and Fr
Page 7 and 8: 4:50 p.m. - 5:00 p.m. Discussion 5:
Page 9 and 10: Poster Presentations Last Names A -
Page 11 and 12: The Role of Ceroid Lipofuscinosis N
Page 13 and 14: A novel Golgi-localized protein inv
Page 15 and 16: 2 The dynamics of SNARE complexes i
Page 17 and 18: 4 Significant divergence in mammali
Page 19 and 20: 6 The Tumoricidal Action of the Ade
Page 21 and 22: 8 LMTK2 Regulates CFTR Recycling in
Page 23 and 24: 10 Sorting in the Golgi Apparatus C
Page 25: 12 Negative regulation of the endoc
Page 29 and 30: 16 An ESCRTs View of Receptor Endoc
Page 31 and 32: 18 GOLPH3 Bridges PtdIns(4)P and My
Page 33 and 34: 20 Novel fluorescent probes to stud
Page 35 and 36: 22 Regulation of Ligand-Independent
Page 37 and 38: 24 A Fifth Adaptor Protein Complex
Page 39 and 40: 26 CATCHR-Family Tethering Complexe
Page 41 and 42: 28 Rab7 localization and activity a
Page 43 and 44: 30 The Drosophila Golgi transmembra
Page 45 and 46: 33 Cbl Amino Acids at a Putative Di
Page 47 and 48: 35 The role of COG subcomplexes in
Page 49 and 50: 37 Mechanism of secretory cargo sor
Page 51 and 52: 39 Understanding the mechanism of G
Page 53 and 54: 41 Mechanisms for selective activat
Page 55 and 56: 44 A novel coat complex traffics me
Page 57 and 58: 46 Membrane trafficking in cytokine
Page 59 and 60: 48 Phosphatidylinositol 4-phosphate
Page 61 and 62: 50 Control of Golgi function by Rab
Page 63 and 64: 52 Adenosine mediated modulation of
Page 65 and 66: 54 Syp1 regulation of actin polymer
Page 67 and 68: 56 Rap1A: A Novel Interactor Involv
Page 69 and 70: 58 Ctage5 is involved in the endopl
Page 71 and 72: 60 A vesicle carrier that mediates
Page 73 and 74: 62 Structural Insights into Dynamin
Page 75 and 76: 64 Identification and interaction m
Page 77 and 78:
66 hRME-6, a rab5GEF that integrate
Page 79 and 80:
68 Assembly of caveolin-1 and cavin
Page 81 and 82:
70 Opposing roles of Annexin A1 and
Page 83 and 84:
72 The role of SNX-BAR proteins in
Page 85 and 86:
74 TRAPP is required for ER exit of
Page 87 and 88:
76 A structural analysis of the ER
Page 89 and 90:
78 Cell cycle-regulated Golgi stack
Page 91 and 92:
80 Rab 14 regulates tight junction
Page 93 and 94:
82 Dissecting the roles of O-glycos
Page 95 and 96:
Author Index - A- Abay, S., 33 Acha
Page 97 and 98:
Marsico, G., 83 Mattera, R., 11 Max
Page 99:
2011 ASBMB Special Symposia Series
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