Biology:ANK2

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A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Ankyrin-B, also known as Ankyrin-2, is a protein which in humans is encoded by the ANK2 gene.[1][2] Ankyrin-B is ubiquitously expressed, but shows high expression in cardiac muscle. Ankyrin-B plays an essential role in the localization and membrane stabilization of ion transporters and ion channels in cardiomyocytes, as well as in costamere structures. Mutations in ankyrin-B cause a dominantly-inherited, cardiac arrhythmia syndrome known as ankyrin-B syndrome as well as sick sinus syndrome; mutations have also been associated to a lesser degree with hypertrophic cardiomyopathy. Alterations in ankyrin-B expression levels are observed in human heart failure.

Structure

Ankyrin-B protein is around 220 kDa, with several isoforms.[3] The ANK2 gene is approximately 560 kb in size and consists of 53 exons on human chromosome 4; ANK2 is also transcriptionally regulated via over 30 alternative splicing events with variable expression of isoforms in cardiac muscle.[4][5][6] Ankyrin-B is a member of the ankyrin family of proteins, and is a modular protein which is composed of three structural domains: an N-terminal domain containing multiple ankyrin repeats; a central region with a highly conserved spectrin binding domain and death domain; and a C-terminal regulatory domain which is the least conserved and subject to variation, and determines ankyrin-B activity.[1][7][8] The membrane-binding region of ankyrin-B is composed of 24 consecutive ankyrin repeats, and it is the membrane-binding domain of ankyrins that confer functional differences among ankyrin isoforms.[8] Though ubiquitously expressed, ankyrin-B shows high expression levels in cardiac muscle, and is expressed 10-fold lower levels in skeletal muscle, suggesting that ankyrin-B plays a specifically adapted functional role in cardiac muscle.[9]

Function

Ankyrin-B is a member of the ankyrin family of proteins. ankyrin-1 has shown to be essential in normal function of erythrocytes;[10] however, ankyrin-B and ankyrin-3 play essential roles in the localization and membrane stabilization of ion transporters and ion channels in cardiomyocytes.[9][11]

Functional insights into ankyrin-B function have come from studies employing ankyrin-B chimeric proteins. One study showed that the death/C-terminal domain of ankyrin-B determines both the subcellular localization as well as activity in restoring normal inositol trisphosphate receptor and ryanodine receptor localization and cardiomyocyte contractility.[8] Further studies have shown that the beta-hairpin loops within the ankyrin repeat domain of ankyrin-B are required for the interaction with the inositol trisphosphate receptor, and a reduction of ankyrin-B in neonatal cardiomyocytes reduces the half-life of the inositol trisphosphate receptor by 3-fold and destabilizes its proper localization; all of these effects were rescued by reintroducing ankyrin-B.[12] Moreover, a specific sequence in ankyrin-B (absent in other ankyrin isoforms) folds as an amphipathic alpha helix is required for normal levels of sodium-calcium exchanger, sodium potassium ATPase and inositol triphosphate receptor in cardiomyocytes, and is regulated by HDJ1/HSP40 binding to this region.[13]

Additional insights into ankyrin-B function have come from studies employing ankyrin-B transgenic animals. Cardiomyocytes from ankyrin-B (-/+) mice exhibited irregular spatial patterns and periodicity of calcium release, as well as abnormal distribution of the sarcomplasmic reticular calcium ATPase, SERCA2, and ryanodine receptors; effects that were rescued by transfection of ankyrin-B.[14] Effects on ryanodine receptors specifically were also rescued by a potent Ca2+/calmodulin-dependent protein kinase II inhibitor, suggesting that inhibition of Ca2+/calmodulin-dependent protein kinase II may also be a potential treatment strategy.[15][16] These mice also display several electrophysiological abnormalities, including bradycardia, variable heart rate, long QT intervals, catecholaminergic polymorphic ventricular tachycardia, syncope, and sudden cardiac death.[17] Mechanistic explanations underlying these effects were explained in a later study conducted in the ankyrin-B (-/+) mice, which showed that reduction of ankyrin-B alters the transport of sodium and calcium and enhances the coupled openings of ryanodine receptors, which results in a higher frequency of calcium sparks and waves of calcium.[18]

It is now becoming clear that ankyrin-B exists in a biomolecular complex with the sodium potassium ATPase, sodium calcium exchanger and inositol triphosphate receptor which is localized in T-tubules within discrete microdomains of cardiomyocytes that are distinct from dyads formed by dihydropyridine receptors complexed to ryanodine receptors. The human ankyrin-B arrhythmogenic mutation (Glu1425Gly) blocks the formation of this complex, which provides a mechanism behind cardiac arrhythmias in patients.[9] Studies from other labs have shed light on the requirement of ankyrin-B in the targeting and post-translational stability of the sodium calcium exchanger in cardiomyocytes, which is clinically important because elevated expression of the sodium calcium exchanger is a factor related to arrhythmia and heart failure.[19] Ankyrin-B forms a membrane complex with ATP-sensitive potassium channels, which is necessary for normal channel trafficking and targeting the channel to sarcolemmal membranes; this interaction is also important in the response of cardiomyocytes to cardiac ischemia and metabolic regulation.[20][21]

Ankyrin-B has also been identified to associate at sarcomeric M-lines and costameres in cardiac muscle and skeletal muscle, respectively. Exon 43′ in ankyrin-B is specifically and predominantly expressed in cardiac muscle and harbors key residues for modulating the interaction between ankyrin-B and obscurin. This interaction is also key for targeting protein phosphatase 2A to cardiac M-lines to propagate phosphorylation signaling paradigms.[22] In skeletal muscle, ankyrin-B interacts with dynactin-4 and with β2-spectrin, which is required for proper localization and functioning of the dystrophin complex and costamere structures, as well as protection from exercise-induced injury.[23]

Clinical Significance

Mutations in the ANK2 gene have been associated with a dominantly-inherited, cardiac arrhythmia syndrome known as ankyrin-B syndrome, previously referred to as long QT syndrome, type 4, which can be described as an atypical arrhythmia syndrome with bradycardia, atrial fibrillation, conduction block, arrhythmia and risk of sudden cardiac death.[24][25][26] Intense investigation is currently ongoing regarding linking ANK2 mutations to the range of severity of cardiac phenotypes, and initial evidence suggests that the varying degrees of loss of function of ankyrin-B protein may explain the effect of any particular mutation.[27][28][29][30][31][32][33][34][35][36]

Initially, a Glu1425Gly mutation in ANK2 was found to cause dominantly-inherited long QT syndrome, type 4, cardiac arrhythmia. The mechanistic underpinnings of this mutation include abnormal expression and targeting of the sodium pump, the sodium-calcium exchanger, and inositol-1,4,5-trisphosphate receptors to transverse tubules, as well as calcium handling resulting in extrasystoles.[37] Further analysis in ANK2 mutations localized in the regulatory domain of ankyrin-2, which is specific to the ankyrin-2 isoform, indicated that long QT syndrome was not a consistent clinical manifestation of ANK2 mutations;[38] however, the effect on Ca(2+) dynamics and localization/expression of the sodium calcium exchanger, sodium potassium ATPase and inositol triphosphate receptor in cardiomyocytes were consistent observations. This study demonstrated that common pathogenic features of all ANK2 mutations was the abnormal coordination of a panel of related ion channels and transporters.[39] Additional mechanistic studies have shown that atrial cardiomyocytes lacking ankyrin-B have shortened action potentials, which can be explained by decreased voltage-dependent calcium channel expression, specifically Ca(v)1.3, which is responsible for low voltage-activated L-type Ca(2+) currents. Ankyrin-B directly associates with and is required for targeting Ca(v)1.3 to membranes.[40]

ANK2 mutations have also been identified in patients with sinus node dysfunction. Mechanistic studies on effects of these mutations in mice showed severe bradycardia and variability in heart rate, as well as dysfunction in ankyrin-B-based trafficking pathways in primary and subsidiary pacemaker cells.[41][42][43] In a large genotype-phenotype study of 874 patients with hypertrophic cardiomyopathy, patients with ANK2 variants exhibited greater maximum left ventricular wall thickness.[44]

In patients with both ischemic and non-ischemic heart failure, ankyrin-B levels are altered. Further mechanistic study showed that reactive oxygen species, intracellular calcium and calpain regulate cardiac ankyrin-B levels, and ankyrin-B is required for normal cardioprotection following ischemia reperfusion injury.[45]

Interactions

References

  1. ↑ 1.0 1.1 "Entrez Gene: ANK2 ankyrin 2, neuronal". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=287. 
  2. ↑ "Mapping of a gene for long QT syndrome to chromosome 4q25-27". Am. J. Hum. Genet. 57 (5): 1114–22. November 1995. PMID 7485162. 
  3. ↑ "Protein sequences of human ANK2 (Uniprot ID Q01484)". https://www.uniprot.org/uniprot/Q01484. 
  4. ↑ Wu, HC; Yamankurt, G; Luo, J; Subramaniam, J; Hashmi, SS; Hu, H; Cunha, SR (24 June 2015). "Identification and characterization of two ankyrin-B isoforms in mammalian heart.". Cardiovascular Research 107 (4): 466–77. doi:10.1093/cvr/cvv184. PMID 26109584. 
  5. ↑ van Oort, RJ; Altamirano, J; Lederer, WJ; Wehrens, XH (December 2008). "Alternative splicing: a key mechanism for ankyrin-B functional diversity?". Journal of Molecular and Cellular Cardiology 45 (6): 709–11. doi:10.1016/j.yjmcc.2008.08.016. PMID 18838078. 
  6. ↑ Cunha, SR; Le Scouarnec, S; Schott, JJ; Mohler, PJ (December 2008). "Exon organization and novel alternative splicing of the human ANK2 gene: implications for cardiac function and human cardiac disease.". Journal of Molecular and Cellular Cardiology 45 (6): 724–34. doi:10.1016/j.yjmcc.2008.08.005. PMID 18790697. 
  7. ↑ Mohler, PJ; Gramolini, AO; Bennett, V (15 April 2002). "Ankyrins.". Journal of Cell Science 115 (Pt 8): 1565–6. doi:10.1242/jcs.115.8.1565. PMID 11950874. 
  8. ↑ 8.0 8.1 8.2 Mohler, PJ; Gramolini, AO; Bennett, V (22 March 2002). "The ankyrin-B C-terminal domain determines activity of ankyrin-B/G chimeras in rescue of abnormal inositol 1,4,5-trisphosphate and ryanodine receptor distribution in ankyrin-B (-/-) neonatal cardiomyocytes.". The Journal of Biological Chemistry 277 (12): 10599–607. doi:10.1074/jbc.m110958200. PMID 11781319. 
  9. ↑ 9.0 9.1 9.2 Mohler, PJ; Davis, JQ; Bennett, V (December 2005). "Ankyrin-B coordinates the Na/K ATPase, Na/Ca exchanger, and InsP3 receptor in a cardiac T-tubule/SR microdomain.". PLOS Biology 3 (12): e423. doi:10.1371/journal.pbio.0030423. PMID 16292983. 
  10. ↑ Eber, SW; Gonzalez, JM; Lux, ML; Scarpa, AL; Tse, WT; Dornwell, M; Herbers, J; Kugler, W et al. (June 1996). "Ankyrin-1 mutations are a major cause of dominant and recessive hereditary spherocytosis.". Nature Genetics 13 (2): 214–8. doi:10.1038/ng0696-214. PMID 8640229. 
  11. ↑ Mohler, PJ; Rivolta, I; Napolitano, C; LeMaillet, G; Lambert, S; Priori, SG; Bennett, V (14 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): 17533–8. doi:10.1073/pnas.0403711101. PMID 15579534. Bibcode: 2004PNAS..10117533M. 
  12. ↑ 12.0 12.1 Mohler, PJ; Davis, JQ; Davis, LH; Hoffman, JA; Michaely, P; Bennett, V (26 March 2004). "Inositol 1,4,5-trisphosphate receptor localization and stability in neonatal cardiomyocytes requires interaction with ankyrin-B.". The Journal of Biological Chemistry 279 (13): 12980–7. doi:10.1074/jbc.m313979200. PMID 14722080. 
  13. ↑ 13.0 13.1 Mohler, PJ; Hoffman, JA; Davis, JQ; Abdi, KM; Kim, CR; Jones, SK; Davis, LH; Roberts, KF et al. (11 June 2004). "Isoform specificity among ankyrins. An amphipathic alpha-helix in the divergent regulatory domain of ankyrin-b interacts with the molecular co-chaperone Hdj1/Hsp40.". The Journal of Biological Chemistry 279 (24): 25798–804. doi:10.1074/jbc.m401296200. PMID 15075330. 
  14. ↑ Tuvia, S; Buhusi, M; Davis, L; Reedy, M; Bennett, V (29 November 1999). "Ankyrin-B is required for intracellular sorting of structurally diverse Ca2+ homeostasis proteins.". The Journal of Cell Biology 147 (5): 995–1008. doi:10.1083/jcb.147.5.995. PMID 10579720. 
  15. ↑ DeGrande, S; Nixon, D; Koval, O; Curran, JW; Wright, P; Wang, Q; Kashef, F; Chiang, D et al. (December 2012). "CaMKII inhibition rescues proarrhythmic phenotypes in the model of human ankyrin-B syndrome.". Heart Rhythm 9 (12): 2034–41. doi:10.1016/j.hrthm.2012.08.026. PMID 23059182. 
  16. ↑ Vatta, M; Chen, PS (December 2012). "CaMKII and ryanodine receptor as new antiarrhythmic targets.". Heart Rhythm 9 (12): 2042–3. doi:10.1016/j.hrthm.2012.09.011. PMID 22982962. 
  17. ↑ Mohler, PJ; Schott, JJ; Gramolini, AO; Dilly, KW; Guatimosim, S; duBell, WH; Song, LS; Haurogné, K et al. (6 February 2003). "Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death.". Nature 421 (6923): 634–9. doi:10.1038/nature01335. PMID 12571597. Bibcode: 2003Natur.421..634M. 
  18. ↑ Camors, E; Mohler, PJ; Bers, DM; Despa, S (June 2012). "Ankyrin-B reduction enhances Ca spark-mediated SR Ca release promoting cardiac myocyte arrhythmic activity.". Journal of Molecular and Cellular Cardiology 52 (6): 1240–8. doi:10.1016/j.yjmcc.2012.02.010. PMID 22406428. 
  19. ↑ Cunha, SR; Bhasin, N; Mohler, PJ (16 February 2007). "Targeting and stability of Na/Ca exchanger 1 in cardiomyocytes requires direct interaction with the membrane adaptor ankyrin-B.". The Journal of Biological Chemistry 282 (7): 4875–83. doi:10.1074/jbc.m607096200. PMID 17178715. 
  20. ↑ Kline, CF; Kurata, HT; Hund, TJ; Cunha, SR; Koval, OM; Wright, PJ; Christensen, M; Anderson, ME et al. (29 September 2009). "Dual role of K ATP channel C-terminal motif in membrane targeting and metabolic regulation.". Proceedings of the National Academy of Sciences of the United States of America 106 (39): 16669–74. doi:10.1073/pnas.0907138106. PMID 19805355. Bibcode: 2009PNAS..10616669K. 
  21. ↑ Li, J; Kline, CF; Hund, TJ; Anderson, ME; Mohler, PJ (10 September 2010). "Ankyrin-B regulates Kir6.2 membrane expression and function in heart.". The Journal of Biological Chemistry 285 (37): 28723–30. doi:10.1074/jbc.m110.147868. PMID 20610380. 
  22. ↑ 22.0 22.1 Cunha, SR; Mohler, PJ (14 November 2008). "Obscurin targets ankyrin-B and protein phosphatase 2A to the cardiac M-line.". The Journal of Biological Chemistry 283 (46): 31968–80. doi:10.1074/jbc.m806050200. PMID 18782775. 
  23. ↑ Ayalon, G; Hostettler, JD; Hoffman, J; Kizhatil, K; Davis, JQ; Bennett, V (4 March 2011). "Ankyrin-B interactions with spectrin and dynactin-4 are required for dystrophin-based protection of skeletal muscle from exercise injury.". The Journal of Biological Chemistry 286 (9): 7370–8. doi:10.1074/jbc.m110.187831. PMID 21186323. 
  24. ↑ Hashemi, SM; Hund, TJ; Mohler, PJ (August 2009). "Cardiac ankyrins in health and disease.". Journal of Molecular and Cellular Cardiology 47 (2): 203–9. doi:10.1016/j.yjmcc.2009.04.010. PMID 19394342. 
  25. ↑ Mohler, PJ (October 2006). "Ankyrins and human disease: what the electrophysiologist should know.". Journal of Cardiovascular Electrophysiology 17 (10): 1153–9. doi:10.1111/j.1540-8167.2006.00540.x. PMID 16800854. 
  26. ↑ Kline, CF; Mohler, PJ (July 2006). "Weighing in on molecular anchors: the role of ankyrin polypeptides in human arrhythmia.". Expert Review of Cardiovascular Therapy 4 (4): 477–85. doi:10.1586/14779072.4.4.477. PMID 16918266. 
  27. ↑ Mohler, PJ; Le Scouarnec, S; Denjoy, I; Lowe, JS; Guicheney, P; Caron, L; Driskell, IM; Schott, JJ et al. (30 January 2007). "Defining the cellular phenotype of "ankyrin-B syndrome" variants: human ANK2 variants associated with clinical phenotypes display a spectrum of activities in cardiomyocytes.". Circulation 115 (4): 432–41. doi:10.1161/circulationaha.106.656512. PMID 17242276. 
  28. ↑ Tomaselli, GF (30 January 2007). "A failure to adapt: ankyrins in congenital and acquired arrhythmias.". Circulation 115 (4): 428–9. doi:10.1161/circulationaha.106.675389. PMID 17261669. 
  29. ↑ Mohler, PJ; Healy, JA; Xue, H; Puca, AA; Kline, CF; Allingham, RR; Kranias, EG; Rockman, HA et al. (17 October 2007). "Ankyrin-B syndrome: enhanced cardiac function balanced by risk of cardiac death and premature senescence.". PLOS ONE 2 (10): e1051. doi:10.1371/journal.pone.0001051. PMID 17940615. Bibcode: 2007PLoSO...2.1051M. 
  30. ↑ Bush, WS; Crawford, DC; Alexander, C; George AL, Jr; Roden, DM; Ritchie, MD (June 2009). "Genetic variation in the rhythmonome: ethnic variation and haplotype structure in candidate genes for arrhythmias.". Pharmacogenomics 10 (6): 1043–53. doi:10.2217/pgs.09.67. PMID 19530973. 
  31. ↑ Sedlacek, K; Stark, K; Cunha, SR; Pfeufer, A; Weber, S; Berger, I; Perz, S; Kääb, S et al. (December 2008). "Common genetic variants in ANK2 modulate QT interval: results from the KORA study.". Circulation: Cardiovascular Genetics 1 (2): 93–9. doi:10.1161/circgenetics.108.792192. PMID 20031550. 
  32. ↑ Alders, M; Christiaans, I; Pagon, RA; Adam, MP; Ardinger, HH; Wallace, SE; Amemiya, A; Bean, LJH et al. (1993). Long QT Syndrome. PMID 20301308. 
  33. ↑ Wolf, RM; Mitchell, CC; Christensen, MD; Mohler, PJ; Hund, TJ (November 2010). "Defining new insight into atypical arrhythmia: a computational model of ankyrin-B syndrome.". American Journal of Physiology. Heart and Circulatory Physiology 299 (5): H1505–14. doi:10.1152/ajpheart.00503.2010. PMID 20729400. 
  34. ↑ Zhang, T; Moss, A; Cong, P; Pan, M; Chang, B; Zheng, L; Fang, Q; Zareba, W et al. (November 2010). "LQTS gene LOVD database.". Human Mutation 31 (11): E1801–10. doi:10.1002/humu.21341. PMID 20809527. 
  35. ↑ Wolf, RM; Glynn, P; Hashemi, S; Zarei, K; Mitchell, CC; Anderson, ME; Mohler, PJ; Hund, TJ (May 2013). "Atrial fibrillation and sinus node dysfunction in human ankyrin-B syndrome: a computational analysis.". American Journal of Physiology. Heart and Circulatory Physiology 304 (9): H1253–66. doi:10.1152/ajpheart.00734.2012. PMID 23436330. Bibcode: 2013BpJ...104S.287W. 
  36. ↑ Robaei, D; Ford, T; Ooi, SY (February 2015). "Ankyrin-B syndrome: a case of sinus node dysfunction, atrial fibrillation and prolonged QT in a young adult.". Heart, Lung & Circulation 24 (2): e31–4. doi:10.1016/j.hlc.2014.09.013. PMID 25456501. 
  37. ↑ "Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death". Nature 421 (6923): 634–9. February 2003. doi:10.1038/nature01335. PMID 12571597. Bibcode: 2003Natur.421..634M. 
  38. ↑ Sherman, J; Tester, DJ; Ackerman, MJ (November 2005). "Targeted mutational analysis of ankyrin-B in 541 consecutive, unrelated patients referred for long QT syndrome genetic testing and 200 healthy subjects.". Heart Rhythm 2 (11): 1218–23. doi:10.1016/j.hrthm.2005.07.026. PMID 16253912. 
  39. ↑ Mohler, PJ; Splawski, I; Napolitano, C; Bottelli, G; Sharpe, L; Timothy, K; Priori, SG; Keating, MT et al. (15 June 2004). "A cardiac arrhythmia syndrome caused by loss of ankyrin-B function.". Proceedings of the National Academy of Sciences of the United States of America 101 (24): 9137–42. doi:10.1073/pnas.0402546101. PMID 15178757. Bibcode: 2004PNAS..101.9137M. 
  40. ↑ Cunha, SR; Hund, TJ; Hashemi, S; Voigt, N; Li, N; Wright, P; Koval, O; Li, J et al. (13 September 2011). "Defects in ankyrin-based membrane protein targeting pathways underlie atrial fibrillation.". Circulation 124 (11): 1212–22. doi:10.1161/circulationaha.111.023986. PMID 21859974. 
  41. ↑ Le Scouarnec, S; Bhasin, N; Vieyres, C; Hund, TJ; Cunha, SR; Koval, O; Marionneau, C; Chen, B et al. (7 October 2008). "Dysfunction in ankyrin-B-dependent ion channel and transporter targeting causes human sinus node disease.". Proceedings of the National Academy of Sciences of the United States of America 105 (40): 15617–22. doi:10.1073/pnas.0805500105. PMID 18832177. Bibcode: 2008PNAS..10515617L. 
  42. ↑ Hund, TJ; Mohler, PJ (2008). "Ankyrin-based targeting pathway regulates human sinoatrial node automaticity.". Channels (Austin, Tex.) 2 (6): 404–6. doi:10.4161/chan.2.6.7220. PMID 19098452. 
  43. ↑ Glukhov, AV; Fedorov, VV; Anderson, ME; Mohler, PJ; Efimov, IR (August 2010). "Functional anatomy of the murine sinus node: high-resolution optical mapping of ankyrin-B heterozygous mice.". American Journal of Physiology. Heart and Circulatory Physiology 299 (2): H482–91. doi:10.1152/ajpheart.00756.2009. PMID 20525877. 
  44. ↑ Lopes, LR; Syrris, P; Guttmann, OP; O'Mahony, C; Tang, HC; Dalageorgou, C; Jenkins, S; Hubank, M et al. (February 2015). "Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy.". Heart 101 (4): 294–301. doi:10.1136/heartjnl-2014-306387. PMID 25351510. 
  45. ↑ Kashef, F; Li, J; Wright, P; Snyder, J; Suliman, F; Kilic, A; Higgins, RS; Anderson, ME et al. (31 August 2012). "Ankyrin-B protein in heart failure: identification of a new component of metazoan cardioprotection.". The Journal of Biological Chemistry 287 (36): 30268–81. doi:10.1074/jbc.m112.368415. PMID 22778271. 
  46. ↑ Mohler, PJ; Yoon, W; Bennett, V (17 September 2004). "Ankyrin-B targets beta2-spectrin to an intracellular compartment in neonatal cardiomyocytes.". The Journal of Biological Chemistry 279 (38): 40185–93. doi:10.1074/jbc.m406018200. PMID 15262991. 
  47. ↑ 47.0 47.1 Ayalon, G; Davis, JQ; Scotland, PB; Bennett, V (26 December 2008). "An ankyrin-based mechanism for functional organization of dystrophin and dystroglycan.". Cell 135 (7): 1189–200. doi:10.1016/j.cell.2008.10.018. PMID 19109891. 
  48. ↑ Davis, JQ; Bennett, V (10 November 1984). "Brain ankyrin. A membrane-associated protein with binding sites for spectrin, tubulin, and the cytoplasmic domain of the erythrocyte anion channel.". The Journal of Biological Chemistry 259 (21): 13550–9. doi:10.1016/S0021-9258(18)90728-3. PMID 6092380. 

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