Ankyrin-3 Explained

Ankyrin-3 (ANK-3), also known as ankyrin-G, is a protein from ankyrin family that in humans is encoded by the ANK3 gene.^{[1] [2]}

Function

The protein encoded by this gene, ankyrin-3 is an immunologically distinct gene product from ankyrins ANK1 and ANK2, and was originally found at the axonal initial segment and nodes of Ranvier of neurons in the central and peripheral nervous systems. Alternatively spliced variants may be expressed in other tissues. Although multiple transcript variants encoding several different isoforms have been found for this gene, the full-length nature of only two have been characterized.^[1]

Within the nervous system, ankyrin-G is specifically localized to the neuromuscular junction, the axon initial segment and the Nodes of Ranvier.^[3] Within the nodes of Ranvier where action potentials are actively propagated, ankyrin-G has long been thought to be the intermediate binding partner to neurofascin and voltage-gated sodium channels.^[4] The genetic deletion of ankyrin-G from multiple neuron types has shown that ankyrin-G is required for the normal clustering of voltage-gated sodium channels at the axon hillock and for action potential firing.^{[5] [6]}

Disease linkage

The ANK3 protein associates with the cardiac sodium channel Na_v1.5 . Both proteins are highly expressed at ventricular intercalated disc and T-tubule membranes in cardiomyocytes. A mutation in the Na_v1.5 protein blocks interaction with ANK3 binding and therefore disrupts surface expression of Na_v1.5 in cardiomyocytes resulting in Brugada syndrome, a type of cardiac arrhythmia.^[7]

Other mutations in the ANK3 gene may be involved in the bipolar disorder and intellectual disability.^{[8] [9] [10] [11]}

Ankyrin family

See main article: Ankyrin. The protein encoded by the ANK3 gene is a member of the ankyrin family of proteins that link the integral membrane proteins to the underlying spectrin-actin cytoskeleton. Ankyrins play key roles in activities such as cell motility, activation, proliferation, contact and the maintenance of specialized membrane domains. Most ankyrins are typically composed of three structural domains: an amino-terminal domain containing multiple ankyrin repeats; a central region with a highly conserved spectrin binding domain; and a carboxy-terminal regulatory domain which is the least conserved and subject to variation.^[1]

Further reading

• Lopez C, Métral S, Eladari D, Drevensek S, Gane P, Chambrey R, Bennett V, Cartron JP, Le Van Kim C, Colin Y . The ammonium transporter RhBG: requirement of a tyrosine-based signal and ankyrin-G for basolateral targeting and membrane anchorage in polarized kidney epithelial cells . The Journal of Biological Chemistry . 280 . 9 . 8221–8228 . March 2005 . 15611082 . 10.1074/jbc.M413351200 . free .
• Kizhatil K, Yoon W, Mohler PJ, Davis LH, Hoffman JA, Bennett V . Ankyrin-G and beta2-spectrin collaborate in biogenesis of lateral membrane of human bronchial epithelial cells . The Journal of Biological Chemistry . 282 . 3 . 2029–2037 . January 2007 . 17074766 . 10.1074/jbc.M608921200 . free .
• Weimer JM, Chattopadhyay S, Custer AW, Pearce DA . Elevation of Hook1 in a disease model of Batten disease does not affect a novel interaction between Ankyrin G and Hook1 . Biochemical and Biophysical Research Communications . 330 . 4 . 1176–1181 . May 2005 . 15823567 . 10.1016/j.bbrc.2005.03.103 .
• Shirahata E, Iwasaki H, Takagi M, Lin C, Bennett V, Okamura Y, Hayasaka K . Ankyrin-G regulates inactivation gating of the neuronal sodium channel, Nav1.6 . Journal of Neurophysiology . 96 . 3 . 1347–1357 . September 2006 . 16775201 . 10.1152/jn.01264.2005 .
• Schulze TG, Detera-Wadleigh SD, Akula N, Gupta A, Kassem L, Steele J, Pearl J, Strohmaier J, Breuer R, Schwarz M, Propping P, Nöthen MM, Cichon S, Schumacher J, Rietschel M, McMahon FJ . Two variants in Ankyrin 3 (ANK3) are independent genetic risk factors for bipolar disorder . Molecular Psychiatry . 14 . 5 . 487–491 . May 2009 . 19088739 . 2793269 . 10.1038/mp.2008.134 .
• Morgan AR, Turic D, Jehu L, Hamilton G, Hollingworth P, Moskvina V, Jones L, Lovestone S, Brayne C, Rubinsztein DC, Lawlor B, Gill M, O'Donovan MC, Owen MJ, Williams J . Association studies of 23 positional/functional candidate genes on chromosome 10 in late-onset Alzheimer's disease . American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics . 144B . 6 . 762–770 . September 2007 . 17373700 . 10.1002/ajmg.b.30509 . 26081707 .
• Morgan AR, Hamilton G, Turic D, Jehu L, Harold D, Abraham R, Hollingworth P, Moskvina V, Brayne C, Rubinsztein DC, Lynch A, Lawlor B, Gill M, O'Donovan M, Powell J, Lovestone S, Williams J, Owen MJ . Association analysis of 528 intra-genic SNPs in a region of chromosome 10 linked to late onset Alzheimer's disease . American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics . 147B . 6 . 727–731 . September 2008 . 18163421 . 10.1002/ajmg.b.30670 . 13916214 .
• Grupe A, Li Y, Rowland C, Nowotny P, Hinrichs AL, Smemo S, Kauwe JS, Maxwell TJ, Cherny S, Doil L, Tacey K, van Luchene R, Myers A, Wavrant-De Vrièze F, Kaleem M, Hollingworth P, Jehu L, Foy C, Archer N, Hamilton G, Holmans P, Morris CM, Catanese J, Sninsky J, White TJ, Powell J, Hardy J, O'Donovan M, Lovestone S, Jones L, Morris JC, Thal L, Owen M, Williams J, Goate A . A scan of chromosome 10 identifies a novel locus showing strong association with late-onset Alzheimer disease . American Journal of Human Genetics . 78 . 1 . 78–88 . January 2006 . 16385451 . 1380225 . 10.1086/498851 .
• Stabach PR, Devarajan P, Stankewich MC, Bannykh S, Morrow JS . Ankyrin facilitates intracellular trafficking of alpha1-Na+-K+-ATPase in polarized cells . American Journal of Physiology. Cell Physiology . 295 . 5 . C1202–C1214 . November 2008 . 18768923 . 2584975 . 10.1152/ajpcell.00273.2008 .
• Sohet F, Colin Y, Genetet S, Ripoche P, Métral S, Le Van Kim C, Lopez C . Phosphorylation and ankyrin-G binding of the C-terminal domain regulate targeting and function of the ammonium transporter RhBG . The Journal of Biological Chemistry . 283 . 39 . 26557–26567 . September 2008 . 18635543 . 3258915 . 10.1074/jbc.M803120200 . free .
• Ignatiuk A, Quickfall JP, Hawrysh AD, Chamberlain MD, Anderson DH . The smaller isoforms of ankyrin 3 bind to the p85 subunit of phosphatidylinositol 3'-kinase and enhance platelet-derived growth factor receptor down-regulation . The Journal of Biological Chemistry . 281 . 9 . 5956–5964 . March 2006 . 16377635 . 10.1074/jbc.M510032200 . free .
• Colland F, Jacq X, Trouplin V, Mougin C, Groizeleau C, Hamburger A, Meil A, Wojcik J, Legrain P, Gauthier JM . Functional proteomics mapping of a human signaling pathway . Genome Research . 14 . 7 . 1324–1332 . July 2004 . 15231748 . 442148 . 10.1101/gr.2334104 .
• Glinsky GV, Berezovska O, Glinskii AB . Microarray analysis identifies a death-from-cancer signature predicting therapy failure in patients with multiple types of cancer . The Journal of Clinical Investigation . 115 . 6 . 1503–1521 . June 2005 . 15931389 . 1136989 . 10.1172/JCI23412 .
• McEwen DP, Meadows LS, Chen C, Thyagarajan V, Isom LL . Sodium channel beta1 subunit-mediated modulation of Nav1.2 currents and cell surface density is dependent on interactions with contactin and ankyrin . The Journal of Biological Chemistry . 279 . 16 . 16044–16049 . April 2004 . 14761957 . 10.1074/jbc.M400856200 . free .
• Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S . Complete sequencing and characterization of 21,243 full-length human cDNAs . Nature Genetics . 36 . 1 . 40–45 . January 2004 . 14702039 . 10.1038/ng1285 . free .
• Wang J, Robinson JF, O'Neil CH, Edwards JY, Williams CM, Huff MW, Pickering JG, Hegele RA . Ankyrin G overexpression in Hutchinson-Gilford progeria syndrome fibroblasts identified through biological filtering of expression profiles . Journal of Human Genetics . 51 . 11 . 934–942 . 2006 . 17033732 . 10.1007/s10038-006-0042-0 . free .
• Kizhatil K, Davis JQ, Davis L, Hoffman J, Hogan BL, Bennett V . Ankyrin-G is a molecular partner of E-cadherin in epithelial cells and early embryos . The Journal of Biological Chemistry . 282 . 36 . 26552–26561 . September 2007 . 17620337 . 10.1074/jbc.M703158200 . free .
• Kizhatil K, Bennett V . Lateral membrane biogenesis in human bronchial epithelial cells requires 190-kDa ankyrin-G . The Journal of Biological Chemistry . 279 . 16 . 16706–16714 . April 2004 . 14757759 . 10.1074/jbc.M314296200 . free .

Notes and References

1. Web site: Entrez Gene: ANK2 ankyrin 3, node of Ranvier .
2. Kapfhamer D, Miller DE, Lambert S, Bennett V, Glover TW, Burmeister M . Chromosomal localization of the ankyrinG gene (ANK3/Ank3) to human 10q21 and mouse 10 . Genomics . 27 . 1 . 189–191 . May 1995 . 7665168 . 10.1006/geno.1995.1023 .
3. Lambert S, Davis JQ, Bennett V . Morphogenesis of the node of Ranvier: co-clusters of ankyrin and ankyrin-binding integral proteins define early developmental intermediates . The Journal of Neuroscience . 17 . 18 . 7025–7036 . September 1997 . 9278538 . 6573274 . 10.1523/JNEUROSCI.17-18-07025.1997 . free .
4. Srinivasan Y, Lewallen M, Angelides KJ . Mapping the binding site on ankyrin for the voltage-dependent sodium channel from brain . The Journal of Biological Chemistry . 267 . 11 . 7483–7489 . April 1992 . 1313804 . 10.1016/S0021-9258(18)42543-4 . free .
5. Zhou D, Lambert S, Malen PL, Carpenter S, Boland LM, Bennett V . AnkyrinG is required for clustering of voltage-gated Na channels at axon initial segments and for normal action potential firing . The Journal of Cell Biology . 143 . 5 . 1295–1304 . November 1998 . 9832557 . 2133082 . 10.1083/jcb.143.5.1295 .
6. Hedstrom KL, Xu X, Ogawa Y, Frischknecht R, Seidenbecher CI, Shrager P, Rasband MN . Neurofascin assembles a specialized extracellular matrix at the axon initial segment . The Journal of Cell Biology . 178 . 5 . 875–886 . August 2007 . 17709431 . 2064550 . 10.1083/jcb.200705119 .
7. Mohler PJ, Rivolta I, Napolitano C, LeMaillet G, Lambert S, Priori SG, Bennett V . Nav1.5 E1053K mutation causing Brugada syndrome blocks binding to ankyrin-G and expression of Nav1.5 on the surface of cardiomyocytes . Proceedings of the National Academy of Sciences of the United States of America . 101 . 50 . 17533–17538 . December 2004 . 15579534 . 536011 . 10.1073/pnas.0403711101 . free . 2004PNAS..10117533M .
8. Web site: Bipolar Disorder Discovery at the Nano Level . 2014-12-01 . dead . https://web.archive.org/web/20141204063840/http://www.yumanewsnow.com/index.php/news/health/8847-bipolar-disorder-discovery-at-the-nano-level . 2014-12-04 .
9. Ferreira MA, O'Donovan MC, Meng YA, Jones IR, Ruderfer DM, Jones L, Fan J, Kirov G, Perlis RH, Green EK, Smoller JW, Grozeva D, Stone J, Nikolov I, Chambert K, Hamshere ML, Nimgaonkar VL, Moskvina V, Thase ME, Caesar S, Sachs GS, Franklin J, Gordon-Smith K, Ardlie KG, Gabriel SB, Fraser C, Blumenstiel B, Defelice M, Breen G, Gill M, Morris DW, Elkin A, Muir WJ, McGhee KA, Williamson R, MacIntyre DJ, MacLean AW, St CD, Robinson M, Van Beck M, Pereira AC, Kandaswamy R, McQuillin A, Collier DA, Bass NJ, Young AH, Lawrence J, Ferrier IN, Anjorin A, Farmer A, Curtis D, Scolnick EM, McGuffin P, Daly MJ, Corvin AP, Holmans PA, Blackwood DH, Gurling HM, Owen MJ, Purcell SM, Sklar P, Craddock N . Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder . Nature Genetics . 40 . 9 . 1056–1058 . September 2008 . 18711365 . 2703780 . 10.1038/ng.209 .
10. Web site: Channeling Mental Illness: GWAS Links Ion Channels, Bipolar Disorder . https://web.archive.org/web/20101218195754/http://schizophreniaforum.org/new/detail.asp?id=1450 . dead . 2010-12-18 . 2008-08-19 . Schizophrenia Research Forum: News . schizophreniaforum.org . 2008-08-21.
11. Iqbal Z, Vandeweyer G, van der Voet M, Waryah AM, Zahoor MY, Besseling JA, Roca LT, Vulto-van Silfhout AT, Nijhof B, Kramer JM, Van der Aa N, Ansar M, Peeters H, Helsmoortel C, Gilissen C, Vissers LE, Veltman JA, de Brouwer AP, Frank Kooy R, Riazuddin S, Schenck A, van Bokhoven H, Rooms L . Homozygous and heterozygous disruptions of ANK3: at the crossroads of neurodevelopmental and psychiatric disorders . Human Molecular Genetics . 22 . 10 . 1960–1970 . May 2013 . 23390136 . 10.1093/hmg/ddt043 . free .