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 Nav1.5 (SCN5A). Both proteins are highly expressed at ventricular intercalated disc and T-tubule membranes in cardiomyocytes. A mutation in the Nav1.5 protein blocks interaction with ANK3 binding and therefore disrupts surface expression of Nav1.5 in cardiomyocytes resulting in Brugada syndrome, a type of cardiac arrhythmia.[7]
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-actincytoskeleton. 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]
↑Kapfhamer D, Miller DE, Lambert S, Bennett V, Glover TW, Burmeister M (May 1995). "Chromosomal localization of the ankyrin-G gene (ANK3/Ank3) to human 10q21 and mouse 10". Genomics. 27 (1): 189–91. doi:10.1006/geno.1995.1023. PMID7665168.
↑Lambert S, Davis JQ, Bennett V (September 1997). "Morphogenesis of the node of Ranvier: co-clusters of ankyrin and ankyrin-binding integral proteins define early developmental intermediates". J. Neurosci. 17 (18): 7025–36. PMID9278538.
↑Srinivasan Y, Lewallen M, Angelides KJ (April 1992). "Mapping the binding site on ankyrin for the voltage-dependent sodium channel from brain". J Biol Chem. 267 (11): 7483–9. PMID1313804.
↑Iqbal, Zafar; Vandeweyer, Geert; van der Voet, Monique; Waryah, Ali Muhammad; Zahoor, Muhammad Yasir; Besseling, Judith A.; Roca, Laura Tomas; Vulto-van Silfhout, Anneke T.; Nijhof, Bonnie; Kramer, Jamie M.; Van der Aa, Nathalie; Ansar, Muhammad; Peeters, Hilde; Helsmoortel, Celine; Gilissen, Christian; Vissers, Lisenka; Veltman, Joris A.; de Brouwer, Arjan P. M.; Kooy, R. Frank; Riazuddin, Sheikh; Schenck, Annette; van Bokhoven, Hans; Rooms, Liesbeth (2013). "Homozygous and heterozygous disruptions of ANK3: at the crossroads of neurodevelopmental and psychiatric disorders". Human Molecular Genetics. 22: 1960–1970. doi:10.1093/hmg/ddt043. ISSN0964-6906. PMID23390136.
Further reading
Lopez C, Métral S, Eladari D, et al. (2005). "The ammonium transporter RhBG: requirement of a tyrosine-based signal and ankyrin-G for basolateral targeting and membrane anchorage in polarized kidney epithelial cells". J. Biol. Chem. 280 (9): 8221–8. doi:10.1074/jbc.M413351200. PMID15611082.
Kizhatil K, Yoon W, Mohler PJ, et al. (2007). "Ankyrin-G and beta2-spectrin collaborate in biogenesis of lateral membrane of human bronchial epithelial cells". J. Biol. Chem. 282 (3): 2029–37. doi:10.1074/jbc.M608921200. PMID17074766.
Weimer JM, Chattopadhyay S, Custer AW, Pearce DA (2005). "Elevation of Hook1 in a disease model of Batten disease does not affect a novel interaction between Ankyrin G and Hook1". Biochem. Biophys. Res. Commun. 330 (4): 1176–81. doi:10.1016/j.bbrc.2005.03.103. PMID15823567.
Shirahata E, Iwasaki H, Takagi M, et al. (2006). "Ankyrin-G regulates inactivation gating of the neuronal sodium channel, Nav1.6". J. Neurophysiol. 96 (3): 1347–57. doi:10.1152/jn.01264.2005. PMID16775201.
Morgan AR, Turic D, Jehu L, et al. (2007). "Association studies of 23 positional/functional candidate genes on chromosome 10 in late-onset Alzheimer's disease". Am. J. Med. Genet. B Neuropsychiatr. Genet. 144B (6): 762–70. doi:10.1002/ajmg.b.30509. PMID17373700.
Morgan AR, Hamilton G, Turic D, et al. (2008). "Association analysis of 528 intra-genic SNPs in a region of chromosome 10 linked to late onset Alzheimer's disease". Am. J. Med. Genet. B Neuropsychiatr. Genet. 147B (6): 727–31. doi:10.1002/ajmg.b.30670. PMID18163421.
Ignatiuk A, Quickfall JP, Hawrysh AD, et al. (2006). "The smaller isoforms of ankyrin 3 bind to the p85 subunit of phosphatidylinositol 3'-kinase and enhance platelet-derived growth factor receptor down-regulation". J. Biol. Chem. 281 (9): 5956–64. doi:10.1074/jbc.M510032200. PMID16377635.
McEwen DP, Meadows LS, Chen C, et al. (2004). "Sodium channel beta1 subunit-mediated modulation of Nav1.2 currents and cell surface density is dependent on interactions with contactin and ankyrin". J. Biol. Chem. 279 (16): 16044–9. doi:10.1074/jbc.M400856200. PMID14761957.
Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID14702039.
Wang J, Robinson JF, O'Neil CH, et al. (2006). "Ankyrin G overexpression in Hutchinson–Gilford progeria syndrome fibroblasts identified through biological filtering of expression profiles". J. Hum. Genet. 51 (11): 934–42. doi:10.1007/s10038-006-0042-0. PMID17033732.
Kizhatil K, Davis JQ, Davis L, et al. (2007). "Ankyrin-G is a molecular partner of E-cadherin in epithelial cells and early embryos". J. Biol. Chem. 282 (36): 26552–61. doi:10.1074/jbc.M703158200. PMID17620337.
Kizhatil K, Bennett V (2004). "Lateral membrane biogenesis in human bronchial epithelial cells requires 190-kDa ankyrin-G". J. Biol. Chem. 279 (16): 16706–14. doi:10.1074/jbc.M314296200. PMID14757759.