Ankyrin-3

Ankyrin-3 (ANK-3), also known as ankyrin-G, is a protein from ankyrin family that in humans is encoded by the ANK3 gene.^[5][6]

ANK3
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4O6X
Identifiers
Aliases	ANK3, ANKYRIN-G, MRT37, ankyrin 3, node of Ranvier (ankyrin G), ankyrin 3
External IDs	OMIM: 600465; MGI: 88026; HomoloGene: 56908; GeneCards: ANK3; OMA:ANK3 - orthologs
Gene location (Human) Chr. Chromosome 10 (human)[1] Band 10q21.2 Start 60,026,298 bp[1] End 60,733,490 bp[1]
Gene location (Mouse) Chr. Chromosome 10 (mouse)[2] Band 10 B5.3|10 36.1 cM Start 69,398,773 bp[2] End 70,027,438 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in endothelial cell Brodmann area 23 dorsal motor nucleus of vagus nerve middle temporal gyrus Region I of hippocampus proper lateral nuclear group of thalamus inferior olivary nucleus postcentral gyrus cerebellar vermis pars compacta Top expressed in lateral geniculate nucleus pontine nuclei ventromedial nucleus mammillary body medial geniculate nucleus lateral hypothalamus olfactory tubercle nucleus accumbens deep cerebellar nuclei anterior amygdaloid area More reference expression data BioGPS n/a
Gene ontology Molecular function protein-macromolecule adaptor activity cadherin binding cytoskeletal protein binding structural constituent of cytoskeleton protein binding spectrin binding transmembrane transporter binding Cellular component cytoplasm cytosol Golgi apparatus cell projection lateral plasma membrane membrane bicellular tight junction T-tubule synapse cell surface axon cell junction basal plasma membrane basolateral plasma membrane endoplasmic reticulum spectrin-associated cytoskeleton sarcolemma lysosome costamere cytoskeleton dendrite postsynaptic membrane sarcoplasmic reticulum neuron projection neuromuscular junction Z discdkac plasma membrane intercalated disc node of Ranvier axon initial segment Biological process regulation of potassium ion transport positive regulation of membrane depolarization during cardiac muscle cell action potential establishment of protein localization mitotic cytokinesis endoplasmic reticulum to Golgi vesicle-mediated transport maintenance of protein location in plasma membrane positive regulation of gene expression positive regulation of sodium ion transport positive regulation of sodium ion transmembrane transporter activity positive regulation of membrane potential plasma membrane organization signal transduction Golgi to plasma membrane protein transport neuromuscular junction development positive regulation of cell communication by electrical coupling positive regulation of homotypic cell-cell adhesion positive regulation of protein targeting to membrane membrane assembly positive regulation of cation channel activity axonogenesis magnesium ion homeostasis neuronal action potential cellular response to magnesium ion protein localization to plasma membrane negative regulation of delayed rectifier potassium channel activity protein localization to axon Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 288 11735 Ensembl ENSG00000151150 ENSMUSG00000069601 UniProt Q12955 G5E8K5 RefSeq (mRNA) NM_001149 NM_001204403 NM_001204404 NM_020987 NM_001320874 NM_009670 NM_146005 NM_170687 NM_170688 NM_170689 NM_170690 NM_170728 NM_170729 NM_170730 RefSeq (protein) NP_001140 NP_001191332 NP_001191333 NP_001307803 NP_066267 NP_033800 NP_666117 NP_733788 NP_733789 NP_733790 NP_733791 NP_733924 NP_733925 NP_733926 Location (UCSC) Chr 10: 60.03 – 60.73 Mb Chr 10: 69.4 – 70.03 Mb PubMed search [3] [4]
Wikidata
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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.^[5]

Within the nervous system, ankyrin-G is specifically localized to the neuromuscular junction, the axon initial segment and the Nodes of Ranvier.^[7] 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.^[8] 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.^[9][10]

Disease linkage

The ANK3 protein associates with the cardiac sodium channel Na_v1.5 (SCN5A). 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.^[11]

Other mutations in the ANK3 gene may be involved in the bipolar disorder and intellectual disability.^{[12][13][14][15]}

Ankyrin family

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.^[5]

References

1. GRCh38: Ensembl release 89: ENSG00000151150 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000069601 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: ANK2 ankyrin 3, node of Ranvier".
6. Kapfhamer D, Miller DE, Lambert S, Bennett V, Glover TW, Burmeister M (May 1995). "Chromosomal localization of the ankyrinG gene (ANK3/Ank3) to human 10q21 and mouse 10". Genomics. 27 (1): 189–191. doi:10.1006/geno.1995.1023. PMID 7665168.
7. 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". The Journal of Neuroscience. 17 (18): 7025–7036. doi:10.1523/JNEUROSCI.17-18-07025.1997. PMC 6573274. PMID 9278538.
8. Srinivasan Y, Lewallen M, Angelides KJ (April 1992). "Mapping the binding site on ankyrin for the voltage-dependent sodium channel from brain". The Journal of Biological Chemistry. 267 (11): 7483–7489. doi:10.1016/S0021-9258(18)42543-4. PMID 1313804.
9. Zhou D, Lambert S, Malen PL, Carpenter S, Boland LM, Bennett V (November 1998). "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. doi:10.1083/jcb.143.5.1295. PMC 2133082. PMID 9832557.
10. Hedstrom KL, Xu X, Ogawa Y, Frischknecht R, Seidenbecher CI, Shrager P, et al. (August 2007). "Neurofascin assembles a specialized extracellular matrix at the axon initial segment". The Journal of Cell Biology. 178 (5): 875–886. doi:10.1083/jcb.200705119. PMC 2064550. PMID 17709431.
11. Mohler PJ, Rivolta I, Napolitano C, LeMaillet G, Lambert S, Priori SG, et al. (December 2004). "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. Bibcode:2004PNAS..10117533M. doi:10.1073/pnas.0403711101. PMC 536011. PMID 15579534.
12. "Bipolar Disorder Discovery at the Nano Level". Archived from the original on 2014-12-04. Retrieved 2014-12-01.
13. Ferreira MA, O'Donovan MC, Meng YA, Jones IR, Ruderfer DM, Jones L, et al. (September 2008). "Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder". Nature Genetics. 40 (9): 1056–1058. doi:10.1038/ng.209. PMC 2703780. PMID 18711365.
14. "Channeling Mental Illness: GWAS Links Ion Channels, Bipolar Disorder". Schizophrenia Research Forum: News. schizophreniaforum.org. 2008-08-19. Archived from the original on 2010-12-18. Retrieved 2008-08-21.
15. Iqbal Z, Vandeweyer G, van der Voet M, Waryah AM, Zahoor MY, Besseling JA, et al. (May 2013). "Homozygous and heterozygous disruptions of ANK3: at the crossroads of neurodevelopmental and psychiatric disorders". Human Molecular Genetics. 22 (10): 1960–1970. doi:10.1093/hmg/ddt043. PMID 23390136.

Further reading

• Lopez C, Métral S, Eladari D, Drevensek S, Gane P, Chambrey R, et al. (March 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". The Journal of Biological Chemistry. 280 (9): 8221–8228. doi:10.1074/jbc.M413351200. PMID 15611082.
• Kizhatil K, Yoon W, Mohler PJ, Davis LH, Hoffman JA, Bennett V (January 2007). "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. doi:10.1074/jbc.M608921200. PMID 17074766.
• Weimer JM, Chattopadhyay S, Custer AW, Pearce DA (May 2005). "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. doi:10.1016/j.bbrc.2005.03.103. PMID 15823567.
• Shirahata E, Iwasaki H, Takagi M, Lin C, Bennett V, Okamura Y, et al. (September 2006). "Ankyrin-G regulates inactivation gating of the neuronal sodium channel, Nav1.6". Journal of Neurophysiology. 96 (3): 1347–1357. doi:10.1152/jn.01264.2005. PMID 16775201.
• Schulze TG, Detera-Wadleigh SD, Akula N, Gupta A, Kassem L, Steele J, et al. (May 2009). "Two variants in Ankyrin 3 (ANK3) are independent genetic risk factors for bipolar disorder". Molecular Psychiatry. 14 (5): 487–491. doi:10.1038/mp.2008.134. PMC 2793269. PMID 19088739.
• Morgan AR, Turic D, Jehu L, Hamilton G, Hollingworth P, Moskvina V, et al. (September 2007). "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. doi:10.1002/ajmg.b.30509. PMID 17373700. S2CID 26081707.
• Morgan AR, Hamilton G, Turic D, Jehu L, Harold D, Abraham R, et al. (September 2008). "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. doi:10.1002/ajmg.b.30670. PMID 18163421. S2CID 13916214.
• Grupe A, Li Y, Rowland C, Nowotny P, Hinrichs AL, Smemo S, et al. (January 2006). "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. doi:10.1086/498851. PMC 1380225. PMID 16385451.
• Stabach PR, Devarajan P, Stankewich MC, Bannykh S, Morrow JS (November 2008). "Ankyrin facilitates intracellular trafficking of alpha1-Na+-K+-ATPase in polarized cells". American Journal of Physiology. Cell Physiology. 295 (5): C1202–C1214. doi:10.1152/ajpcell.00273.2008. PMC 2584975. PMID 18768923.
• Sohet F, Colin Y, Genetet S, Ripoche P, Métral S, Le Van Kim C, et al. (September 2008). "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. doi:10.1074/jbc.M803120200. PMC 3258915. PMID 18635543.
• Ignatiuk A, Quickfall JP, Hawrysh AD, Chamberlain MD, Anderson DH (March 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". The Journal of Biological Chemistry. 281 (9): 5956–5964. doi:10.1074/jbc.M510032200. PMID 16377635.
• Colland F, Jacq X, Trouplin V, Mougin C, Groizeleau C, Hamburger A, et al. (July 2004). "Functional proteomics mapping of a human signaling pathway". Genome Research. 14 (7): 1324–1332. doi:10.1101/gr.2334104. PMC 442148. PMID 15231748.
• Glinsky GV, Berezovska O, Glinskii AB (June 2005). "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. doi:10.1172/JCI23412. PMC 1136989. PMID 15931389.
• McEwen DP, Meadows LS, Chen C, Thyagarajan V, Isom LL (April 2004). "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. doi:10.1074/jbc.M400856200. PMID 14761957.
• Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, et al. (January 2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nature Genetics. 36 (1): 40–45. doi:10.1038/ng1285. PMID 14702039.
• Wang J, Robinson JF, O'Neil CH, Edwards JY, Williams CM, Huff MW, et al. (2006). "Ankyrin G overexpression in Hutchinson-Gilford progeria syndrome fibroblasts identified through biological filtering of expression profiles". Journal of Human Genetics. 51 (11): 934–942. doi:10.1007/s10038-006-0042-0. PMID 17033732.
• Kizhatil K, Davis JQ, Davis L, Hoffman J, Hogan BL, Bennett V (September 2007). "Ankyrin-G is a molecular partner of E-cadherin in epithelial cells and early embryos". The Journal of Biological Chemistry. 282 (36): 26552–26561. doi:10.1074/jbc.M703158200. PMID 17620337.
• Kizhatil K, Bennett V (April 2004). "Lateral membrane biogenesis in human bronchial epithelial cells requires 190-kDa ankyrin-G". The Journal of Biological Chemistry. 279 (16): 16706–16714. doi:10.1074/jbc.M314296200. PMID 14757759.

External links

• ANK3+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Human ANK3 genome location and ANK3 gene details page in the UCSC Genome Browser.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.