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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 湯志永 | zh_TW |
dc.contributor.advisor | en | |
dc.contributor.author | 傅斯如 | zh_TW |
dc.contributor.author | Ssu-Ju Fu | en |
dc.date.accessioned | 2021-06-17T03:42:29Z | - |
dc.date.available | 2023-12-07 | - |
dc.date.copyright | 2018-03-29 | - |
dc.date.issued | 2018 | - |
dc.date.submitted | 2002-01-01 | - |
dc.identifier.citation | A Krol H, Krawczyk P, S Bosch K, A Aten J, Hol E, Reits E (2008) Polyglutamine Expansion Accelerates the Dynamics of Ataxin-1 and Does Not Result in Aggregate Formation.
Abrahamsen H, O'Neill AK, Kannan N, Kruse N, Taylor SS, Jennings PA, Newton AC (2012) Peptidyl-prolyl Isomerase Pin1 Controls Down-regulation of Conventional Protein Kinase C Isozymes. Journal of Biological Chemistry 287:13262-13278. Abriel H, Staub O (2005) Ubiquitylation of Ion Channels. Physiology 20:398-407. Adhikari A, Chen ZJ (2009) Diversity of Polyubiquitin Chains. Developmental Cell 16:485-486. Altier C, Garcia-Caballero A, Simms B, You H, Chen L, Walcher J, Tedford HW, Hermosilla T, Zamponi GW (2011) The Cav[beta] subunit prevents RFP2-mediated ubiquitination and proteasomal degradation of L-type channels. Nat Neurosci 14:173-180. Anckar J, Sistonen L (2007) SUMO: getting it on. Biochemical Society Transactions 35:1409. Anderson DD, Eom JY, Stover PJ (2012) Competition between Sumoylation and Ubiquitination of Serine Hydroxymethyltransferase 1 Determines Its Nuclear Localization and Its Accumulation in the Nucleus. Journal of Biological Chemistry 287:4790-4799. Antonelli R, Pizzarelli R, Pedroni A, Fritschy J-M, del sal G, Cherubini E, Zacchi P (2014) Pin1-dependent signalling negatively affects GABAergic transmission by modulating neuroligin2/gephyrin interaction. Antonelli R, De Filippo R, Middei S, Stancheva S, Pastore B, Ammassari-Teule M, Barberis A, Cherubini E, Zacchi P (2016) Pin1 Modulates the Synaptic Content of NMDA Receptors via Prolyl-Isomerization of PSD-95. The Journal of Neuroscience 36:5437. B Kordasiewicz H, M Thompson R, Brent Clark H, Gomez C (2006) C-termini of P/Q-type Ca2+ channel alpha1A subunits translocate to nuclei and promote polyglutamine-mediated toxicity. Baloh RW (2012) Episodic ataxias 1 and 2. Handbook of Clinical Neurology 103:595-602. Barrett CF, Rittenhouse AR (2000) Modulation of N-type calcium channel activity by G-proteins and protein kinase C. J Gen Physiol 115:277-286. Birault V, Solari R, Hanrahan J, Thomas DY (2013) Correctors of the basic trafficking defect of the mutant F508del-CFTR that causes cystic fibrosis. Current Opinion in Chemical Biology 17:353-360. Bloom J, Amador V, Bartolini F, DeMartino G, Pagano M (2003) Proteasome-Mediated Degradation of p21 via N-Terminal Ubiquitinylation. Cell 115:71-82. Blume-Jensen P, Hunter T (2001) Oncogenic kinase signalling. Nature 411:355-365. Cantí C, Nieto-Rostro M, Foucault I, Heblich F, Wratten J, Richards MW, Hendrich J, Douglas L, Page KM, Davies A, Dolphin AC (2005) The metal-ion-dependent adhesion site in the Von Willebrand factor-A domain of α2δ subunits is key to trafficking voltage-gated Ca2+ channels. Proceedings of the National Academy of Sciences of the United States of America 102:11230-11235. Catterall WA (2000) Structure and Regulation of Voltage-Gated Ca2+ Channels. Annual Review of Cell and Developmental Biology 16:521-555. Catterall WA (2011) Voltage-Gated Calcium Channels. Cold Spring Harbor Perspectives in Biology 3. Catterall WA, Perez-Reyes E, Snutch TP, Striessnig J (2005) International Union of Pharmacology. XLVIII. Nomenclature and Structure-Function Relationships of Voltage-Gated Calcium Channels. Pharmacological Reviews 57:411. Chen Y, Deng L, Maeno-Hikichi Y, Lai M, Chang S, Chen G, Zhang J-f (2003) Formation of an Endophilin-Ca2+ Channel Complex Is Critical for Clathrin-Mediated Synaptic Vesicle Endocytosis. Cell 115:37-48. Claessen JHL, Kundrat L, Ploegh HL (2012) Protein quality control in the ER: balancing the ubiquitin checkbook. Trends in Cell Biology 22:22-32. Cohen P (2002) The origins of protein phosphorylation. Nat Cell Biol 4:E127-E130. Crenshaw DG, Yang J, Means AR, Kornbluth S (1998) The mitotic peptidyl-prolyl isomerase, Pin1, interacts with Cdc25 and Plx1. The EMBO journal 17:1315-1327. Dahimene S, Page KM, Nieto-Rostro M, Pratt WS, D'Arco M, Dolphin AC (2016) A CaV2.1 N-terminal fragment relieves the dominant-negative inhibition by an Episodic ataxia 2 mutant. Neurobiology of Disease 93:243-256. Deshaies RJ, Joazeiro CAP (2009) RING Domain E3 Ubiquitin Ligases. Annual Review of Biochemistry 78:399-434. Du X, Wang J, Zhu H, Rinaldo L, Lamar K-M, Palmenberg Ann C, Hansel C, Gomez Christopher M (2013) Second Cistron in CACNA1A Gene Encodes a Transcription Factor Mediating Cerebellar Development and SCA6. Cell 154:118-133. Ducros A, Denier C, Joutel A, Cecillon M, Lescoat C, Vahedi K, Darcel F, Vicaut E, Bousser M-G, Tournier-Lasserve E (2001) The Clinical Spectrum of Familial Hemiplegic Migraine Associated with Mutations in a Neuronal Calcium Channel. New England Journal of Medicine 345:17-24. Flotho A, Melchior F (2013) Sumoylation: A Regulatory Protein Modification in Health and Disease. Annual Review of Biochemistry 82:357-385. Frontali M (2001) Spinocerebellar ataxia type 6: channelopathy or glutamine repeat disorder? Brain Research Bulletin 56:227-231. Fu S-J, Jeng C-J, Ma C-H, Peng Y-J, Lee C-M, Fang Y-C, Lee Y-C, Tang S-C, Hu M-C, Tang C-Y (2017) Ubiquitin Ligase RNF138 Promotes Episodic Ataxia Type 2-Associated Aberrant Degradation of Human Cav2.1 (P/Q-Type) Calcium Channels. The Journal of Neuroscience 37:2485. Göthel SF, Marahiel MA (1999) Peptidyl-prolyl cis-trans isomerases, a superfamily of ubiquitous folding catalysts. Cellular and Molecular Life Sciences CMLS 55:423-436. Geiss-Friedlander R, Melchior F (2007) Concepts in sumoylation: a decade on. Nature Reviews Molecular Cell Biology 8:947. Geoffroy M-C, Hay R (2009) An additional role for SUMO in ubiquitin-mediated proteolysis. Ghosh S, May MJ, Kopp EB (1998) NF-κB AND REL PROTEINS: Evolutionarily Conserved Mediators of Immune Responses. Annual Review of Immunology 16:225-260. Gill G (2004) SUMO and ubiquitin in the nucleus: different functions, similar mechanisms? Genes & Development 18:2046-2059. Gomez CM, Thompson RM, Gammack JT, Perlman SL, Dobyns WB, Truwit CL, Zee DS, Clark HB, Anderson JH (1997) Spinocerebellar ataxia type 6: Gaze-evoked and vertical nystagmus, Purkinje cell degeneration, and variable age of onset. Annals of Neurology 42:933-950. Graves TD, Imbrici P, Kors EE, Terwindt GM, Eunson LH, Frants RR, Haan J, Ferrari MD, Goadsby PJ, Hanna MG, van den Maagdenberg AMJM, Kullmann DM (2008) Premature stop codons in a facilitating EF-hand splice variant of CaV2.1 cause episodic ataxia type 2. Neurobiology of Disease 32:10-15. Greer PL, Hanayama R, Bloodgood BL, Mardinly AR, Lipton DM, Flavell SW, Kim T-K, Griffith EC, Waldon Z, Maehr R, Ploegh HL, Chowdhury S, Worley PF, Steen J, Greenberg ME (2010) The Angelman Syndrome Protein Ube3A Regulates Synapse Development by Ubiquitinating Arc. Cell 140:704-716. Guerriero CJ, Brodsky JL (2012) The delicate balance between secreted protein folding and endoplasmic reticulum-associated degradation in human physiology. Physiological reviews 92:537-576. Hans M, Luvisetto S, Williams ME, Spagnolo M, Urrutia A, Tottene A, Brust PF, Johnson EC, Harpold MM, Stauderman KA, Pietrobon D (1999) Functional Consequences of Mutations in the Human α<sub>1A</sub> Calcium Channel Subunit Linked to Familial Hemiplegic Migraine. The Journal of Neuroscience 19:1610. Hebert DN, Molinari M (2007) In and Out of the ER: Protein Folding, Quality Control, Degradation, and Related Human Diseases. Physiological Reviews 87:1377. Hell JW, Yokoyama CT, Breeze LJ, Chavkin C, Catterall WA (1995) Phosphorylation of presynaptic and postsynaptic calcium channels by cAMP-dependent protein kinase in hippocampal neurons. The EMBO Journal 14:3036-3044. Hendriks IA, D’Souza RCJ, Yang B, Verlaan-de Vries M, Mann M, Vertegaal ACO (2014) Uncovering Global SUMOylation Signaling Networks in a Site-Specific Manner. Nature structural & molecular biology 21:927-936. Hetz C, Glimcher LH (2011) Protein homeostasis networks in physiology and disease. Current opinion in cell biology 23:123-125. Higley MJ, Sabatini BL (2012) Calcium Signaling in Dendritic Spines. Cold Spring Harbor Perspectives in Biology 4. Hille B, Beech DJ, Bernheim L, Mathie A, Shapiro MS, Wollmuth LP (1995) Multiple G-protein-coupled pathways inhibit N-type Ca channels of neurons. Life Sciences 56:989-992. Ho Lee T, Pastorino L, Lu KP (2011) Peptidyl-prolyl cis-trans isomerase Pin1 in ageing, cancer and Alzheimer disease. Holderith N, Lorincz A, Katona G, Rozsa B, Kulik A, Watanabe M, Nusser Z (2012) Release probability of hippocampal glutamatergic terminals scales with the size of the active zone. Nat Neurosci 15:988-997. Hood JK, Silver PA (1999) In or out? Regulating nuclear transport. Current Opinion in Cell Biology 11:241-247. Hoppa MB, Lana B, Margas W, Dolphin AC, Ryan TA (2012) [agr]2[dgr] expression sets presynaptic calcium channel abundance and release probability. Nature 486:122-125. Huang TT, Wuerzberger-Davis SM, Wu Z-H, Miyamoto S (2003) Sequential Modification of NEMO/IKKgamma by SUMO-1 and Ubiquitin Mediates NF-kappaB Activation by Genotoxic Stress. Cell 115:565-576. Hunter T, Karin M (1992) The regulation of transcription by phosphorylation. Cell 70:375-387. Indriati DW, Kamasawa N, Matsui K, Meredith AL, Watanabe M, Shigemoto R (2013) Quantitative Localization of Ca<sub>v</sub>2.1 (P/Q-Type) Voltage-Dependent Calcium Channels in Purkinje Cells: Somatodendritic Gradient and Distinct Somatic Coclustering with Calcium-Activated Potassium Channels. The Journal of Neuroscience 33:3668. Irwin S, Vandelft M, Pinchev D, Howell JL, Graczyk J, Orr HT, Truant R (2005) RNA association and nucleocytoplasmic shuttling by ataxin-1. Journal of Cell Science 118:233. Ishiguro T, Ishikawa K, Takahashi M, Obayashi M, Amino T, Sato N, Sakamoto M, Fujigasaki H, Tsuruta F, Dolmetsch R, Arai T, Sasaki H, Nagashima K, Kato T, Yamada M, Takahashi H, Hashizume Y, Mizusawa H (2010) The carboxy-terminal fragment of α1A calcium channel preferentially aggregates in the cytoplasm of human spinocerebellar ataxia type 6 Purkinje cells. Ishikawa K, Watanabe M, Yoshizawa K, Fujita T, Iwamoto H, Yoshizawa T, Harada K, Nakamagoe K, Komatsuzaki Y, Satoh A, Doi M, Ogata T, Kanazawa I, Shoji S, Mizusawa H (1999) Clinical, neuropathological, and molecular study in two families with spinocerebellar ataxia type 6 (SCA6). Journal of Neurology, Neurosurgery & Psychiatry 67:86. Ishikawa K, Owada K, Ishida K, Fujigasaki H, Shun Li M, Tsunemi T, Ohkoshi N, Toru S, Mizutani T, Hayashi M, Arai N, Hasegawa K, Kawanami T, Kato T, Makifuchi T, Shoji S, Tanabe T, Mizusawa H (2001) Cytoplasmic and nuclear polyglutamine aggregates in SCA6 Purkinje cells. Neurology 56:1753-1756. J Adams P, Garcia E, S David L, Mulatz K, D Spacey S, Snutch T (2009) Ca V 2.1 P/Q-type calcium channel alternative splicing affects the functional impact of familial hemiplegic migraine mutations: Implications for calcium channelopathies. Jackson SP (1992) Regulating transcription factor activity by phosphorylation. Trends in Cell Biology 2:104-108. Jen J, Kim GW, Baloh RW (2004) Clinical spectrum of episodic ataxia type 2. Neurology 62:17-22. Jen J, Wan J, Graves M, Yu H, Mock AF, Coulin CJ, Kim G, Yue Q, Papazian DM, Baloh RW (2001) Loss-of-function EA2 mutations are associated with impaired neuromuscular transmission. Neurology 57:1843-1848. Jen JC, Graves TD, Hess EJ, Hanna MG, Griggs RC, Baloh RW (2007) Primary episodic ataxias: diagnosis, pathogenesis and treatment. Brain 130:2484-2493. Jeng C-J, Chen Y-T, Chen Y-W, Tang C-Y (2006) Dominant-negative effects of human P/Q-type Ca<sup>2+</sup> channel mutations associated with episodic ataxia type 2. American Journal of Physiology - Cell Physiology 290:C1209. Jeng C-J, Sun M-C, Chen Y-W, Tang C-Y (2008) Dominant-negative effects of episodic ataxia type 2 mutations involve disruption of membrane trafficking of human P/Q-type Ca2+ channels. Journal of Cellular Physiology 214:422-433. Jouvenceau A, Eunson LH, Spauschus A, Ramesh V, Zuberi SM, Kullmann DM, Hanna MG (2001) Human epilepsy associated with dysfunction of the brain P/Q-type calcium channel. The Lancet 358:801-807. Kühnle S, Mothes B, Matentzoglu K, Scheffner M (2013) Role of the ubiquitin ligase E6AP/UBE3A in controlling levels of the synaptic protein Arc. Proceedings of the National Academy of Sciences 110:8888-8893. Kaeser PS, Deng L, Wang Y, Dulubova I, Liu X, Rizo J, Südhof TC (2011) RIM Proteins Tether Ca2+ Channels to Presynaptic Active Zones via a Direct PDZ-Domain Interaction. Cell 144:282-295. Kamp TJ, Hell JW (2000) Regulation of Cardiac L-Type Calcium Channels by Protein Kinase A and Protein Kinase C. Circulation Research 87:1095-1102. Kim JH, Park S-M, Kang MR, Oh S-Y, Lee TH, Muller MT, Chung IK (2005) Ubiquitin ligase MKRN1 modulates telomere length homeostasis through a proteolysis of hTERT. Genes & Development 19:776-781. Kleiger G, Mayor T (2014) Perilous journey: a tour of the ubiquitin–proteasome system. Trends in Cell Biology 24:352-359. Koester HJ, Sakmann B (2000) Calcium dynamics associated with action potentials in single nerve terminals of pyramidal cells in layer 2/3 of the young rat neocortex. The Journal of Physiology 529:625-646. Komar AA, Hatzoglou M (2005) Internal Ribosome Entry Sites in Cellular mRNAs: Mystery of Their Existence. Journal of Biological Chemistry 280:23425-23428. Komar AA, Hatzoglou M (2011) Cellular IRES-mediated translation: The war of ITAFs in pathophysiological states. Cell Cycle 10:229-240. Kravtsova-Ivantsiv Y, Ciechanover A (2012) Non-canonical ubiquitin-based signals for proteasomal degradation. Journal of Cell Science 125:539. Kubodera T, Yokota T, Ohwada K, Ishikawa K, Miura H, Matsuoka T, Mizusawa H (2003) Proteolytic cleavage and cellular toxicity of the human α1A calcium channel in spinocerebellar ataxia type 6. Kulik Á, Nakadate K, Hagiwara A, Fukazawa Y, Luján R, Saito H, Suzuki N, Futatsugi A, Mikoshiba K, Frotscher M, Shigemoto R (2004) Immunocytochemical localization of the α1A subunit of the P/Q-type calcium channel in the rat cerebellum. European Journal of Neuroscience 19:2169-2178. Lee A, Westenbroek RE, Haeseleer F, Palczewski K, Scheuer T, Catterall WA (2002) Differential modulation of Cav2.1 channels by calmodulin and Ca2+-binding protein 1. Nat Neurosci 5:210-217. Liebelt F, Vertegaal ACO (2016) Ubiquitin-dependent and independent roles of SUMO in proteostasis. American Journal of Physiology-Cell Physiology 311:C284-C296. Lineberry N, Su L, Soares L, Fathman CG (2008) The Single Subunit Transmembrane E3 Ligase Gene Related to Anergy in Lymphocytes (GRAIL) Captures and Then Ubiquitinates Transmembrane Proteins across the Cell Membrane. Journal of Biological Chemistry 283:28497-28505. Liou Y-C, Zhou XZ, Lu KP (2011) Prolyl isomerase Pin1 as a molecular switch to determine the fate of phosphoproteins. Trends in Biochemical Sciences 36:501-514. Lipscombe D, Allen SE, Toro CP (2013) Control of neuronal voltage-gated calcium ion channels from RNA to protein. Trends in Neurosciences 36:598-609. Long P, Samnakay P, Jenner P, Rose S (2012) A yeast two-hybrid screen reveals that osteopontin associates with MAP1A and MAP1B in addition to other proteins linked to microtubule stability, apoptosis and protein degradation in the human brain. European Journal of Neuroscience 36:2733-2742. Lu KP, Zhou XZ (2007) The prolyl isomerase PIN1: a pivotal new twist in phosphorylation signalling and disease. 8:904. Lu KP, Hanes SD, Hunter T (1996) A human peptidyl-prolyl isomerase essential for regulation of mitosis. Nature 380:544-547. Lu KP, Liou Y-C, Vincent I (2003) Proline-directed phosphorylation and isomerization in mitotic regulation and in Alzheimer's Disease. Lu KP, Finn G, Lee TH, Nicholson LK (2007) Prolyl cis-trans isomerization as a molecular timer. 3:619. Lu P-J, Zhou XZ, Liou Y-C, Noel JP, Lu KP (2002) Critical Role of WW Domain Phosphorylation in Regulating Phosphoserine Binding Activity and Pin1 Function. Journal of Biological Chemistry 277:2381-2384. Lu Z, Hunter T (2014) Prolyl isomerase Pin1 in cancer. Cell Research 24:1033-1049. Lufei C, Cao X (2009) Nuclear import of Pin1 is mediated by a novel sequence in the PPIase domain. FEBS Letters 583:271-276. Lukacs GL, Verkman AS (2012) CFTR: folding, misfolding and correcting the ΔF508 conformational defect. Trends in Molecular Medicine 18:81-91. Lussier MP, Nasu-Nishimura Y, Roche KW (2011) Activity-Dependent Ubiquitination of the AMPA Receptor Subunit GluA2. The Journal of Neuroscience 31:3077. Lussier MP, Herring BE, Nasu-Nishimura Y, Neutzner A, Karbowski M, Youle RJ, Nicoll RA, Roche KW (2012) Ubiquitin ligase RNF167 regulates AMPA receptor-mediated synaptic transmission. Proceedings of the National Academy of Sciences 109:19426-19431. Müller S, Hoege C, Pyrowolakis G, Jentsch S (2001) Sumo, ubiquitin's mysterious cousin. Nature Reviews Molecular Cell Biology 2:202. Mabb Angela M, Je HS, Wall Mark J, Robinson Camenzind G, Larsen Rylan S, Qiang Y, Corrêa Sonia AL, Ehlers Michael D (2014) Triad3A Regulates Synaptic Strength by Ubiquitination of Arc. Neuron 82:1299-1316. MacGurn JA, Hsu P-C, Emr SD (2012) Ubiquitin and Membrane Protein Turnover: From Cradle to Grave. Annual Review of Biochemistry 81:231-259. Manning G, Plowman GD, Hunter T, Sudarsanam S (2002) Evolution of protein kinase signaling from yeast to man. Trends in Biochemical Sciences 27:514-520. Mantuano E, Veneziano L, Jodice C, Frontali M (2003) Spinocerebellar ataxia type 6 and episodic ataxia type 2: differences and similarities between two allelic disorders. Cytogenetic and Genome Research 100:147-153. Mantuano E, Romano S, Veneziano L, Gellera C, Castellotti B, Caimi S, Testa D, Estienne M, Zorzi G, Bugiani M, Rajabally YA, Barcina MJG, Servidei S, Panico A, Frontali M, Mariotti C (2010) Identification of novel and recurrent CACNA1A gene mutations in fifteen patients with episodic ataxia type 2. Journal of the Neurological Sciences 291:30-36. Mark MD, Krause M, Boele H-J, Kruse W, Pollok S, Kuner T, Dalkara D, Koekkoek S, De Zeeuw CI, Herlitze S (2015) Spinocerebellar Ataxia Type 6 Protein Aggregates Cause Deficits in Motor Learning and Cerebellar Plasticity. The Journal of Neuroscience 35:8882. Matsuyama Z, Wakamori M, Mori Y, Kawakami H, Nakamura S, Imoto K (1999) Direct alteration of the P/Q-type Ca2+ channel property by polyglutamine expansion in spinocerebellar ataxia 6. McHugh D, Sharp EM, Scheuer T, Catterall WA (2000) Inhibition of cardiac L-type calcium channels by protein kinase C phosphorylation of two sites in the N-terminal domain. Proceedings of the National Academy of Sciences of the United States of America 97:12334-12338. Mezghrani A, Monteil A, Watschinger K, Sinnegger-Brauns MJ, Barrère C, Bourinet E, Nargeot J, Striessnig J, Lory P (2008) A Destructive Interaction Mechanism Accounts for Dominant-Negative Effects of Misfolded Mutants of Voltage-Gated Calcium Channels. The Journal of Neuroscience 28:4501. Mokrejš M, Mašek T, Vopálenský V, Hlubuček P, Delbos P, Pospíšek M (2010) IRESite—a tool for the examination of viral and cellular internal ribosome entry sites. Nucleic Acids Research 38:D131-D136. Moretto Zita M, Marchionni I, Bottos E, Righi M, Del Sal G, Cherubini E, Zacchi P (2007) Post-phosphorylation prolyl isomerisation of gephyrin represents a mechanism to modulate glycine receptors function. The EMBO Journal 26:1761-1771. Nachbauer W, Nocker M, Karner E, Stankovic I, Unterberger I, Eigentler A, Schneider R, Poewe W, Delazer M, Boesch S (2014) Episodic ataxia type 2: phenotype characteristics of a novel CACNA1A mutation and review of the literature. Journal of Neurology 261:983-991. Ophoff RA, Terwindt GM, Vergouwe MN, van Eijk R, Oefner PJ, Hoffman SMG, Lamerdin JE, Mohrenweiser HW, Bulman DE, Ferrari M, Haan J, Lindhout D, van Ommen G-JB, Hofker MH, Ferrari MD, Frants RR (1996) Familial Hemiplegic Migraine and Episodic Ataxia Type-2 Are Caused by Mutations in the Ca2+ Channel Gene CACNL1A4. Cell 87:543-552. Orr HT, Chung M-y, Banfi S, Kwiatkowski Jr TJ, Servadio A, Beaudet AL, McCall AE, Duvick LA, Ranum LPW, Zoghbi HY (1993) Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nature Genetics 4:221. Page KM, Rothwell SW, Dolphin AC (2016) The CaVβ Subunit Protects the I-II Loop of the Voltage-gated Calcium Channel CaV2.2 from Proteasomal Degradation but Not Oligoubiquitination. Journal of Biological Chemistry 291:20402-20416. Page KM, Heblich F, Davies A, Butcher AJ, Leroy J, Bertaso F, Pratt WS, Dolphin AC (2004) Dominant-Negative Calcium Channel Suppression by Truncated Constructs Involves a Kinase Implicated in the Unfolded Protein Response. The Journal of Neuroscience 24:5400. Page KM, Heblich F, Margas W, Pratt WS, Nieto-Rostro M, Chaggar K, Sandhu K, Davies A, Dolphin AC (2010) N Terminus Is Key to the Dominant Negative Suppression of CaV2 Calcium Channels: IMPLICATIONS FOR EPISODIC ATAXIA TYPE 2. Journal of Biological Chemistry 285:835-844. Pawson T, Scott JD (2005) Protein phosphorylation in signaling – 50 years and counting. Trends in Biochemical Sciences 30:286-290. Pietrobon D (2010) CaV2.1 channelopathies. Pflügers Archiv - European Journal of Physiology 460:375-393. Pranke IM, Sermet-Gaudelus I (2014) Biosynthesis of cystic fibrosis transmembrane conductance regulator. The International Journal of Biochemistry & Cell Biology 52:26-38. R. Plummer M, Logothetis D, Hess P (1989) Elementary properties and pharmacological sensitivities of calcium channels in mammalian peripheral neurons. Raike RS, Kordasiewicz HB, Thompson RM, Gomez CM (2007) Dominant-negative suppression of Cav2.1 currents by α12.1 truncations requires the conserved interaction domain for β subunits. Molecular and Cellular Neuroscience 34:168-177. Rajakulendran S, Kaski D, Hanna MG (2012) Neuronal P/Q-type calcium channel dysfunction in inherited disorders of the CNS. Nat Rev Neurol 8:86-96. Riley BE, Zoghbi HY, Orr HT (2005) SUMOylation of the Polyglutamine Repeat Protein, Ataxin-1, Is Dependent on a Functional Nuclear Localization Signal. Journal of Biological Chemistry 280:21942-21948. Rippmann JF, Hobbie S, Daiber C, Guilliard B, Bauer M, Birk J, Nar H, Garin-Chesa P, Rettig WJ, Schnapp A (2000) Phosphorylation-dependent Proline Isomerization Catalyzed by Pin1 Is Essential for Tumor Cell Survival and Entry into Mitosis. Cell Growth Differ 11:409-416. Rodriguez MS, Dargemont C, Hay RT (2001) SUMO-1 Conjugation in Vivo Requires Both a Consensus Modification Motif and Nuclear Targeting. Journal of Biological Chemistry 276:12654-12659. Rose SJ, Kriener LH, Heinzer AK, Fan X, Raike RS, van den Maagdenberg AMJM, Hess EJ (2014) The first knockin mouse model of episodic ataxia type 2. Experimental Neurology 261:553-562. Rotin D, Kumar S (2009) Physiological functions of the HECT family of ubiquitin ligases. Nat Rev Mol Cell Biol 10:398-409. Saegusa H, Wakamori M, Matsuda Y, Wang J, Mori Y, Zong S, Tanabe T (2007) Properties of human Cav2.1 channel with a spinocerebellar ataxia type 6 mutation expressed in Purkinje cells. Molecular and Cellular Neuroscience 34:261-270. Sakurai T, Hell JW, Woppmann A, Miljanich GP, Catterall WA (1995) Immunochemical Identification and Differential Phosphorylation of Alternatively Spliced Forms of the α1A Subunit of Brain Calcium Channels. Journal of Biological Chemistry 270:21234-21242. Sakurai T, Westenbroek RE, Rettig J, Hell J, Catterall WA (1996) Biochemical properties and subcellular distribution of the BI and rbA isoforms of alpha 1A subunits of brain calcium channels. The Journal of Cell Biology 134:511. Sampson DA, Wang M, Matunis MJ (2001) The Small Ubiquitin-like Modifier-1 (SUMO-1) Consensus Sequence Mediates Ubc9 Binding and Is Essential for SUMO-1 Modification. Journal of Biological Chemistry 276:21664-21669. Schwarz LA, Hall BJ, Patrick GN (2010) Activity-Dependent Ubiquitination of GluA1 Mediates a Distinct AMPA Receptor Endocytosis and Sorting Pathway. The Journal of Neuroscience 30:16718. Servadio A, Koshy B, Armstrong D, Antalffy B, Orr HT, Zoghbi HY (1995) Expression analysis of the ataxin–1 protein in tissues from normal and spinocerebellar ataxia type 1 individuals. Nature Genetics 10:94. Shen M, Stukenberg P, W. Kirschner M, Lu KP (1998) The essential mitotic peptidyl-prolyl isomerase Pin1 binds and regulates mitosis-specific phosphoproteins. Sheng J, He L, Zheng H, Xue L, Luo F, Shin W, Sun T, Kuner T, Yue DT, Wu L-G (2012) Calcium-channel number critically influences synaptic strength and plasticity at the active zone. Nat Neurosci 15:998-1006. Soong TW, DeMaria CD, Alvania RS, Zweifel LS, Liang MC, Mittman S, Agnew WS, Yue DT (2002) Systematic Identification of Splice Variants in Human P/Q-Type Channel α1 2.1 Subunits: Implications for Current Density and Ca<sup>2+</sup>-Dependent Inactivation. The Journal of Neuroscience 22:10142. Tai H-C, Schuman EM (2008) Ubiquitin, the proteasome and protein degradation in neuronal function and dysfunction. Nat Rev Neurosci 9:826-838. Takahashi M, Obayashi M, Ishiguro T, Sato N, Niimi Y, Ozaki K, Mogushi K, Mahmut Y, Tanaka H, Tsuruta F, Dolmetsch R, Yamada M, Takahashi H, Kato T, Mori O, Eishi Y, Mizusawa H, Ishikawa K (2013) Cytoplasmic Location of α1A Voltage-Gated Calcium Channel C-Terminal Fragment (Cav2.1-CTF) Aggregate Is Sufficient to Cause Cell Death. Tedford HW, Zamponi GW (2006) Direct G Protein Modulation of Cav2 Calcium Channels. Pharmacological Reviews 58:837. Toru S, Murakoshi T, Ishikawa K, Saegusa H, Fujigasaki H, Uchihara T, Nagayama S, Osanai M, Mizusawa H, Tanabe T (2000) Spinocerebellar Ataxia Type 6 Mutation Alters P-type Calcium Channel Function. Journal of Biological Chemistry 275:10893-10898. Tottene A, Fellin T, Pagnutti S, Luvisetto S, Striessnig J, Fletcher C, Pietrobon D (2002) Familial hemiplegic migraine mutations increase Ca2+ influx through single human CaV2.1 channels and decrease maximal CaV2.1 current density in neurons. Proceedings of the National Academy of Sciences 99:13284-13289. Tsai N-P (2014) Ubiquitin proteasome system-mediated degradation of synaptic proteins: An update from the postsynaptic side. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1843:2838-2842. Tsai YC, M Weissman A (2011) Ubiquitylation in ERAD: Reversing to go Forward? Tsou W-L, Qiblawi SH, Hosking RR, Gomez CM, Todi SV (2016) Polyglutamine length-dependent toxicity from α1ACT in Drosophila models of spinocerebellar ataxia type 6. Biology Open 5:1770. Vembar SS, Brodsky JL (2008) One step at a time: endoplasmic reticulum-associated degradation. Nat Rev Mol Cell Biol 9:944-957. Veneziano L, Albertosi S, Pesci D, Mantuano E, Frontali M, Jodice C (2011) Dramatically different levels of cacna1a gene expression between pre-weaning wild type and leaner mice. Journal of the Neurological Sciences 305:71-74. Vlastaridis P, Kyriakidou P, Chaliotis A, Van de Peer Y, Oliver SG, Amoutzias GD (2017) Estimating the total number of phosphoproteins and phosphorylation sites in eukaryotic proteomes. GigaScience 6:1-11. Volk S, Wang M, Pickart CM (2005) Chemical and Genetic Strategies for Manipulating Polyubiquitin Chain Structure. Methods in Enzymology 399:3-20. W Anderson T, Wright C, Brooks W (2010) The E3 Ubiquitin Ligase NARF Promotes Colony Formation in vitro and Exhibits Enhanced Expression Levels in Glioblastoma Multiforme in vivo. Waithe D, Ferron L, Page KM, Chaggar K, Dolphin AC (2011) β-Subunits Promote the Expression of CaV2.2 Channels by Reducing Their Proteasomal Degradation. Journal of Biological Chemistry 286:9598-9611. Wan J, Mamsa H, Johnston J, Spriggs E, Singer H, Zee D, Al-Bayati A, Baloh R, Jen J (2011) Large Genomic Deletions in CACNA1A Cause Episodic Ataxia Type 2. Frontiers in Neurology 2. Wappl E, Koschak A, Poteser M, Sinnegger MJ, Walter D, Eberhart A, Groschner K, Glossmann H, Kraus RL, Grabner M, Striessnig J (2002) Functional Consequences of P/Q-type Ca2+Channel Cav2.1 Missense Mutations Associated with Episodic Ataxia Type 2 and Progressive Ataxia. Journal of Biological Chemistry 277:6960-6966. Watase K, Barrett CF, Miyazaki T, Ishiguro T, Ishikawa K, Hu Y, Unno T, Sun Y, Kasai S, Watanabe M, Gomez CM, Mizusawa H, Tsien RW, Zoghbi HY (2008) Spinocerebellar ataxia type 6 knockin mice develop a progressive neuronal dysfunction with age-dependent accumulation of mutant CaV2.1 channels. Proceedings of the National Academy of Sciences 105:11987-11992. Wei S et al. (2015) Active Pin1 is a key target of all-trans retinoic acid in acute promyelocytic leukemia and breast cancer. Nat Med 21:457-466. Weis K (1998) Importins and exportins: how to get in and out of the nucleus. Trends in Biochemical Sciences 23:185-189. Welcker M, Orian A, Jin J, Grim JA, Harper JW, Eisenman RN, Clurman BE (2004) The Fbw7 tumor suppressor regulates glycogen synthase kinase 3 phosphorylation-dependent c-Myc protein degradation. Proceedings of the National Academy of Sciences of the United States of America 101:9085-9090. Westenbroek RE, Sakurai T, Elliott EM, Hell JW, Starr TV, Snutch TP, Catterall WA (1995) Immunochemical identification and subcellular distribution of the alpha 1A subunits of brain calcium channels. The Journal of Neuroscience 15:6403. Westmark PR, Westmark CJ, Wang S, Levenson J, O’Riordan KJ, Burger C, Malter JS (2010) Pin1 and PKMζ Sequentially Control Dendritic Protein Synthesis. Science Signaling 3:ra18. Whitmarsh AJ, Davis RJ (2000) Regulation of transcription factor function by phosphorylation. Cellular and Molecular Life Sciences CMLS 57:1172-1183. William S. Brooks SBaDFC (2014) RNF138/NARF is a cell cycle regulated E3 ligase that polyubiquitinates G2E3. JSM Cell & Developmental Biology 2(1). Wulf G, Finn G, Suizu F, Lu KP (2005) Phosphorylation-specific prolyl isomerization: is there an underlying theme? Nat Cell Biol 7:435-441. Yabe I, Sasaki H, Matsuura T, Takada A, Akemi W, Suzuki Y, Fukazawa T, Hamada T, Oda T, Ohnishi A, Tashiro K (1998) SCA6 mutation analysis in a large cohort of the Japanese patients with late-onset pure cerebellar ataxia. Journal of the Neurological Sciences 156:89-95. Yamada M, Ohnishi J, Ohkawara B, Iemura S, Satoh K, Hyodo-Miura J, Kawachi K, Natsume T, Shibuya H (2006) NARF, an Nemo-like Kinase (NLK)-associated Ring Finger Protein Regulates the Ubiquitylation and Degradation of T Cell Factor/Lymphoid Enhancer Factor (TCF/LEF). Journal of Biological Chemistry 281:20749-20760. Yeh E, Means A (2007) PIN1, the cell cycle and cancer. Yeh E, Cunningham M, Arnold H, Chasse D, Monteith T, Ivaldi G, C Hahn W, Stukenberg P, Shenolikar S, Uchida T, M Counter C, Nevins J, Means A, Sears R (2004) Yeh E, Cunningham M, Arnold H, Chasse D, Monteith T, Ivaldi G, Hahn WC, Stukenberg PT, Shenolikar S, Uchida T, Counter CM, Nevins JR, Means AR and Sears RA signalling pathway controlling c-Myc degradation that impacts oncogenic transformation of human cells. Nat. Cell. Biol. 6: 308-318. Yeh ES, Lew BO, Means AR (2006) The Loss of PIN1 Deregulates Cyclin E and Sensitizes Mouse Embryo Fibroblasts to Genomic Instability. Journal of Biological Chemistry 281:241-251. Yu-Wai-Man P, Gorman G, Bateman DE, Leigh RJ, Chinnery PF (2009) Vertigo and vestibular abnormalities in spinocerebellar ataxia type 6. Journal of Neurology 256:78-82. Zamponi GW, Currie KPM (2013) Regulation of CaV2 calcium channels by G protein coupled receptors. Biochimica et Biophysica Acta (BBA) - Biomembranes 1828:1629-1643. Zandi E, Karin M (1999) Bridging the Gap: Composition, Regulation, and Physiological Function of the IκB Kinase Complex. Zhang Y, Helm JS, Senatore A, Spafford JD, Kaczmarek LK, Jonas EA (2008) PKC-Induced Intracellular Trafficking of Ca<sub>V</sub>2 Precedes Its Rapid Recruitment to the Plasma Membrane. The Journal of Neuroscience 28:2601. Zhao Q, Xie Y, Zheng Y, Jiang S, Liu W, Mu W, Liu Z, Zhao Y, Xue Y, Ren J (2014) GPS-SUMO: a tool for the prediction of sumoylation sites and SUMO-interaction motifs. Nucleic Acids Research 42:W325-W330. Zhou Y-x, Chen S-s, Wu T-f, Ding D-d, Chen X-h, Chen J-m, Su Z-p, Li B, Chen G-l, Xie X-s, Dai Y-f, Wei Y-x, Du Z-w (2012) A Novel Gene RNF138 Expressed in Human Gliomas and Its Function in the Glioma Cell Line U251. Analytical Cellular Pathology 35. Zhu J, Shibasaki F, Price R, Guillemot J-C, Yano T, Dötsch V, Wagner G, Ferrara P, McKeon F (1998) Intramolecular Masking of Nuclear Import Signal on NF-AT4 by Casein Kinase I and MEKK1. Cell 93:851-861. Zhuchenko O, Bailey J, Bonnen P, Ashizawa T, Stockton DW, Amos C, Dobyns WB, Subramony SH, Zoghbi HY, Lee CC (1997) Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the α1A-voltage-dependent calcium channel. Nature Genetics 15:62. Zoghbi HY, Orr HT (2000) Glutamine Repeats and Neurodegeneration. Annual Review of Neuroscience 23:217-247. | - |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/70081 | - |
dc.description.abstract | 電壓控制型鈣離子通道CaV2.1,由α1A次單元以及α2δ、β4 附屬單元組成功能性的鈣離子通道,其在調控神經傳導物質釋放與調節神經突觸訊號傳遞上扮演重要角色。當人類CaV2.1基因(CACNA1A)帶有突變時,可能會導致第一型家族性偏頭痛(familial hemiplegic migraine-1; FHM-1)、第二型遺傳性共濟失調(episodic ataxia type 2 (EA2)、以及第6型脊髓小腦萎縮症(spinocerebellar ataxia type 6; SCA6)。文獻指出,當CaV2.1帶有EA2疾病突變時,會使得突變蛋白質的穩定度下降,甚至引起顯性抑制作用(dominant-negative suppression)而使得正常型蛋白質經proteasome進行降解。因此,我們試圖找出調控CaV2.1蛋白質降解之途徑。
我們確立了E3泛素連接酶RNF138與CaV2.1間的交互作用,RNF138與CaV2.1共同表現在神經細胞之突觸前後。共同表現RNF138會促進CaV2.1之泛素化,並加速CaV2.1蛋白質降解速度。相反的,降低細胞內生性RNF138表現,會顯著增加CaV2.1蛋白質表現量並提升CaV2.1蛋白質穩定度,也會有效的增加EA2突變型蛋白質,並且改善由EA2突變型引起的蛋白質表現量顯性抑制作用。然而利用電生理進行CaV2.1離子通道功能測試時卻發現,降低內生性RNF138表現量僅能部分回復由EA2突變型所引起的電流抑制作用。利用biotinylation實驗觀察,降低內生性RNF138表現,雖然改善了EA2突變型對CaV2.1 WT的蛋白質抑制作用,但仍然無法改變由EA2突變型所導致的CaV2.1 WT trafficking降低的問題。 除了RNF138之外,我們還確立了Pin1與CaV2.1間的交互作用。與RNF138類似,Pin1與CaV2.1也共同表現在神經細胞之突觸前後。我們發現,CaV2.1蛋白質表現量會受到其磷酸化程度所調控。Pin1會促進CaV2.1之泛素化,並加速CaV2.1蛋白質降解速度。利用Pin1阻斷劑,抑制細胞內生性Pin1活性,會顯著增加CaV2.1蛋白質表現量,以及增加CaV2.1蛋白質穩定度。有趣的是,相較於CaV2.1正常型,Pin1與EA2突變型有較高的親合力。統合實驗結果我們推論,Pin1扮演上游調控分子,並參與在由RNF138媒介的CaV2.1蛋白質降解途徑中。 CACNA1A mRNA具有除了promotor以外的內生性ribosome結合位(internal ribosomal entry site; IRES) 。CACNA1A基因bicistronic的特性,會使得mRNA轉譯出全長的CaV2.1鈣離子通道與僅具有CaV2.1部分羧基端片段的carboxyl-terminal fragment (CTF)。當CTF含有過度延長的polyglutamine時,會導致遺傳性第6型脊髓小腦萎縮症。實驗發現,CTF較全長CaV2.1次單元蛋白質表現量低,然而卻有較穩定的蛋白質半衰期。與CaV2.1次單元相同,CTF蛋白質也是經由proteasome進行降解,並依然受到Pin1與RNF138調控。CTF會受到SUMOylation的修飾作用,或許與CTF在細胞內分布的位置有關,然而這是未來我們需要進一步釐清的問題。 總結此篇論文發現,我們認為Pin1與RNF138在調控CaV2.1蛋白質表現與離子通道功能上扮演著重要的角色。利用調整內生性Pin1與RNF138之功能,進一步調控CaV2.1的蛋白質表現量,或許可以提供未來治療EA2與SCA6疾病的可能契機。 | zh_TW |
dc.description.abstract | Voltage-gated Ca2+ (CaV) channels comprise a pore-forming α1A subunit with auxiliary α2δ and β subunits. CaV2.1 (P/Q-type) channels play an essential role in regulating synaptic signaling. Mutations in CACNA1A, the human gene encoding the CaV2.1 subunit, are associated with the neurological disease familial hemiplegic migraine-1 (FHM-1), episodic ataxia type 2 (EA2), and spinocerebellar ataxia type 6 (SCA6). Several EA2-causing mutants exhibit impaired protein stability and exert dominant-negative suppression of CaV2.1 wild-type (WT) protein expression via aberrant proteasomal degradation. Here, we set out to delineate the protein degradation mechanism of human CaV2.1.
We identified RNF138, an E3 ubiquitin ligase, as a novel CaV2.1-binding partner. In neurons, RNF138 and CaV2.1 coexist in the same protein complex and display notable subcellular colocalization at presynaptic and postsynaptic regions. Overexpression of RNF138 promotes polyubiquitination and accelerates protein turnover of CaV2.1. Disrupting endogenous RNF138 function significantly upregulates the CaV2.1 protein level, enhances CaV2.1 protein stability, and effectively rescues the defective protein expression of EA2 mutants, as well as fully reversing EA2 mutant-induced excessive proteasomal degradation of CaV2.1 WT subunits. However, only partially restores the dominant-negative effect of EA2 mutants on CaV2.1 WT functional expression, which can be attributed to defective membrane trafficking of CaV2.1 WT in the presence of EA2 mutants. We also identified Pin1, a peptidyl-prolyl cis/trans isomerase, as another novel CaV2.1-binding partner. Like RNF138, Pin1 colocalizes with CaV2.1 in neurons at both presynaptic and postsynaptic region. We demonstrated a phosphorylation-dependent change in CaV2.1 protein level. Pin1 promotes polyubiquitination and accelerates protein turnover of CaV2.1, and application of a specific Pin1 blocker leads to enhanced CaV2.1 protein level. Interestingly, Pin1 exhibits a significantly higher affinity to an EA2 mutant than CaV2.1 WT. Take together Pin1 appears to act as an upstream regulator for the RNF138-mediated CaV2.1 degradation pathway. The CACNA1A gene has a cryptic internal ribosomal entry site (IRES). The bicistronic mRNA of CACNA1A gene encodes the full-length CaV2.1 protein, as well as the CaV2.1 carboxyl-terminal fragment (CTF) that harbors polyglutamine repeats implicated in the pathogenesis of SCA6. We demonstrate that the CaV2.1 CTF has lower expression protein level, but longer protein half-life, than full-length CaV2.1 subunit. The protein degradation of CaV2.1 CTF is also via proteasome and is regulated by Pin1 and RNF138. The posttranslational modification of CaV2.1 CTF may also involve SUMOylation, which may regulate its subcellular localization. Overall, we conclude that Pin1 and RNF138 play a critical role in the homeostatic regulation of CaV2.1 protein level and functional expression. Regulation CaV2.1 protein level via specific modulator of endogenous Pin1 and RNF138 function may potentially contribute to future development of novel therapeutic strategies for CaV2.1-related disease such as EA2 and SCA6. | en |
dc.description.provenance | Made available in DSpace on 2021-06-17T03:42:29Z (GMT). No. of bitstreams: 1 ntu-107-D01441001-1.pdf: 11584293 bytes, checksum: 6fdc8aef513ee5f4f573fe28093c32cf (MD5) Previous issue date: 2018 | en |
dc.description.tableofcontents | 摘要 i
Abstract iii 目錄 v Chapter 1 Introduction 1 Supplementary Table S1-1. Subunit composition and function of voltage-gated CaV2+ channel types. 6 Supplementary Figure S1-2. Topology of the CaV2.1 voltage-gated channel. 7 Supplementary Table S1-3. Clinical and genetic features of disease associated with mutants in CACNA1A gene. 8 Supplementary Figure S1-4. Steps in endoplasmic reticulum-associated degradation (ERAD). 9 Chapter 2 Materials and methods 11 2.1 Molecular Biology 11 2.2 Primers for Site-Directed mutagenesis 12 2.3 The molecular weight in CaV2.1 constructs 16 2.4 Glutathione S-transferase (GST) pull-down assay 16 2.5 Cell culture and transient expression 18 2.6 Immunoblotting 19 2.7 Immunoprecipitation 21 2.8 Rat brain lysates and subcellular fractionation 21 2.9 Cortical neuron cultures 22 2.10 Immunofluorescence 23 2.11 Lentivirus infection 24 2.12 RT-PCR 26 2.12.1 RNA extraction 26 2.12.2 DNaseI digestion 26 2.12.3 RT-PCR 27 2.13 Cycloheximide chase 28 2.14 Protein ubiquitination analyses 29 2.15 Biotinylation of cell surface protein 29 2.16 Two electrode voltage clamp 30 2.17 Whole cell patch clamp 31 2.18 Statistic analysis 32 Chapter 3. RNF138 is the E3 ubiquitin ligase of human CaV2.1 channel. 33 3.1 Introduction 33 3.2 Results 36 3.2.1 Interaction and colocalization of RNF138 with CaV2.1 in neurons 36 3.2.2 RNF138 is an E3 ubiquitin ligase of CaV2.1 39 3.2.3 RNF138 mediates proteasomal degradation of EA2-causing CaV2.1 mutants 43 3.2.4 RNF138 controls functional expression of CaV2.1 channel 44 3.2.5 RNF138 contributes to the dominant-negative effect of EA2 mutants on CaV2.1 WT 46 3.3 Discussion 48 3.4 Figures 54 Figure 3-1. RNF138 is a novel binding partner of CaV2.1 subunit. 54 Figure 3-2. Colocalization of RNF138 and CaV2.1 in neurons. 58 Figure 3-3. Regulation of CaV2.1 protein expression by RNF138. 62 Figure 3-4. RNF138 reduces CaV2.1 protein stability. 65 Figure 3-5. RNF138 promotes CaV2.1 polyubiquitination. Biochemical demonstration of CaV2.1 polyubiquitination in HEK293T cells. 68 Figure 3-6. Auxiliary subunits protect CaV2.1 from RNF138-mediated protein degradation. 71 Figure 3-7. RNF138 regulates protein level of EA2-causing CaV2.1 mutants. 73 Figure 3-8. RNF138 mediates protein degradation of EA2 mutants. 76 Figure 3-9. RNF138 attenuates surface expression of CaV2.1. 79 Figure 3-10. RNF138 suppresses functional expression of CaV2.1. 82 Figure 3-11. RNF138 promotes EA2 mutant-induced degradation of CaV2.1 WT subunits. 85 Chapter 4. Pin1 mediated protein quality control of human CaV2.1 channel. 87 4.1 Introduction 87 4.2 Results 91 4.2.1 Interaction and localization of Pin1 and CaV2.1 in neurons 91 4.2.2 Pin1 reduces CaV2.1 protein stability 92 4.2.3 Pin1 controls the expression level of CaV2.1 channel 94 4.2.4 Phosphorylation influences CaV2.1 protein level 95 4.2.5 Pin1 regulates CaV2.1 upstream to RNF138-mediated ER-associated degradation pathway. 97 4.2.6 The auxiliary α2δ and β4a subunits compete with Pin1 in ER-mediated regulation of CaV2.1. 98 4.2.7 Implication of Pin1 in EA2-associated aberrant degradation of CaV2.1. 99 4.3 Discussion 101 4.4 Figures 107 Figure 4-1. Interaction and colocalization of Pin1 and CaV2.1. 108 Figure 4-2. Regulation of CaV2.1 protein expression by Pin1. 112 Figure 4-3. Pin1 reduces CaV2.1 protein stability. 115 Figure 4-4. Pin1 suppresses functional expression of CaV2.1 channel. 116 Figure 4-5. Phosphorylation-dependent regulation of CaV2.1 protein level. 118 Figure 4-6. Pin1 as the upstream regulator of CaV2.1 protein ubiquitination. 121 Figure 4-7. Auxiliary subunits protect CaV2.1 from Pin1-enhanced protein degradation. 124 Figure 4-8. Pin1 regulates protein level of the EA2-causing CaV2.1 mutant F1406C. 127 Figure 4-9. A model of the ER quality control system for CaV2.1 channel. 129 Chapter 5. Pin1 and RNF138 regulate the carboxyl-terminal fragment of human CaV2.1 channel. 130 5.1 Introduction 130 Supplemental Figure S5-1. Predicted secondary structure of CACNA1A IRES and corresponding protein fragment. 134 5.2 Result 135 5.2.1 The expression pattern on CaV2.1 CTF and CTC. 135 5.2.2 Pin1 regulates CaV2.1 CTC protein level. 135 5.2.3 RNF138 mediates proteasomal degradation of CaV2.1 CTC 136 5.2.4 Nuclear localization of CaV2.1 CTC. 137 5.3 Discussion 139 5.4 Figures 145 Figure 5-1. Characterization of CaV2.1 carboxyl-terminal fragment (CTF) and carboxyl-terminal construct (CTC). 145 Figure 5-2. Regulation of CaV2.1 CTC protein level by Pin1. 147 Figure 5-3. ATRA increases CaV2.1 CTF and CTC protein level. 149 Figure 5-4. Ub-K0 increases CaV2.1 CTF and CTC protein level. 150 Figure 5-5. RNF138 suppresses CaV2.1 CTC protein level. 151 Figure 5-6. CaV2.1 CTC is more stable than the full-length protein. 153 Figure 5-7. Subcellular localization of CaV2.1-long and CTC-long. 155 Figure 5-8. Potential SUMOylation of CaV2.1 CTC. 156 Figure 5-9. A hypothetical model for the regulation of protein degradation and nuclear translocation of CaV2.1 CTF. 157 Chapter 6. Summary and Conclusion 158 Chapter 7. Refence 161 | - |
dc.language.iso | en | - |
dc.title | 探討人類Cav2.1鈣離子通道蛋白之降解機制 | zh_TW |
dc.title | Regulation of human P/Q-type calcium (Cav2.1) channel degradation. | en |
dc.type | Thesis | - |
dc.date.schoolyear | 106-1 | - |
dc.description.degree | 博士 | - |
dc.contributor.oralexamcommittee | 鄭瓊娟;陳建璋;陳瑞華;李怡萱;湯頌君 | zh_TW |
dc.contributor.oralexamcommittee | ;;;; | en |
dc.subject.keyword | 鈣離子,泛素,E3連接?, | zh_TW |
dc.subject.keyword | Calcium channel,ubiquitin,E3 ligase, | en |
dc.relation.page | 174 | - |
dc.identifier.doi | 10.6342/NTU201800380 | - |
dc.rights.note | 未授權 | - |
dc.date.accepted | 2018-02-07 | - |
dc.contributor.author-college | 醫學院 | - |
dc.contributor.author-dept | 生理學研究所 | - |
顯示於系所單位: | 生理學科所 |
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