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8.A.28 The Ankyrin (Ankyrin) Family

Ankyrin-B (Ank2, ankyrin-2; 3924 aas) interacts directly with and is required for targeting and stability of the Na+/Ca2+ exchanger 1 in cardiomyocytes (Cunha et al., 2007). It is also required for assembly of the Na+,K+ ATPase and various membrane receptors and transporters (Liu et al., 2008).  Exon organization and alternative splicing give rise to at least 30 ANK2 mRNA transcripts.  The ANK2 gene consists of 53 exons spanning ~560 kbps (Cunha et al., 2008).  

Ankyrins are a family of adaptor proteins which associate with a group of structurally diverse ion channels and transporters including the Na/Ca exchanger (Li et al., 1993; Mohler et al., 2003; Mohler et al., 2005), the Na/K ATPase, voltage-gated Na+ channels, and the anion exchanger. Multiple lines of evidence predict a role for ankyrin polypeptides in the proper localization and stability of the Na/Ca exchanger at the cardiomyocyte plasma membrane. Ankyrin polypeptides directly bind to the cardiac Na/Ca exchanger with high affinity (Li et al., 1993; Mohler et al., 2005).

Ankyrins have N-terminal Ank repeat units that are homologous to those of channel proteins in families 1.A.4 and 1.A.1. These repeats of about 100 residues, comprise of ankyrin B. They generally attach integral membrane proteins to cytoskeletal proteins. They are regulated by phosphorylation. Defects in Ank2 cause sick sinus syndrome with bradycardia (also called 'human sinus node dysfunction (SND)) (Le Scouarnec et al., 2008).

References associated with 8.A.28 family:

Cunha, S.R., N. Bhasin, and P.J. Mohler. (2007). Targeting and stability of Na/Ca Exchanger 1 in cardiomyocytes requires direct interaction with the membrane adaptor ankyrin-B. J. Biol. Chem. 282: 4875-4883. 17178715
Cunha, S.R., S. Le Scouarnec, J.J. Schott, and P.J. Mohler. (2008). Exon organization and novel alternative splicing of the human ANK2 gene: implications for cardiac function and human cardiac disease. J Mol. Cell Cardiol 45: 724-734. 18790697
Desmond, P.F., A. Labuza, J. Muriel, M.L. Markwardt, A.E. Mancini, M.A. Rizzo, and R.J. Bloch. (2017). Interactions between Small Ankyrin 1 and Sarcolipin Coordinately Regulate Activity of the Sarco(endo)plasmic Reticulum Ca2+-ATPase (SERCA1). J. Biol. Chem. [Epub: Ahead of Print] 28487373
Desmond, P.F., J. Muriel, M.L. Markwardt, M.A. Rizzo, and R.J. Bloch. (2015). Identification of Small Ankyrin 1 as a Novel Sarco(endo)plasmic Reticulum Ca2+-ATPase 1 (SERCA1) Regulatory Protein in Skeletal Muscle. J. Biol. Chem. 290: 27854-27867. 26405035
Dulhunty, A.F., L. Wei-LaPierre, M.G. Casarotto, and N.A. Beard. (2016). The Core Skeletal Muscle Ryanodine Receptor Calcium Release Complex. Clin Exp Pharmacol Physiol. [Epub: Ahead of Print] 27696487
El-Dessouky, S.H., M.Y. Issa, M.M. Aboulghar, H.M. Gaafar, A.E. Elarab, M.I. Ateya, H.H. Omar, C. Beetz, and M.S. Zaki. (2020). Prenatal delineation of a distinct lethal fetal syndrome caused by a homozygous truncating KIDINS220 variant. Am J Med Genet A. [Epub: Ahead of Print] 32909676
Gergs, U., T. Berndt, J. Buskase, L.R. Jones, U. Kirchhefer, F.U. Müller, K.D. Schlüter, W. Schmitz, and J. Neumann. (2007). On the role of junctin in cardiac Ca2+ handling, contractility, and heart failure. Am. J. Physiol. Heart Circ Physiol 293: H728-734. 17400717
Goonasekera, S.A., N.A. Beard, L. Groom, T. Kimura, A.D. Lyfenko, A. Rosenfeld, I. Marty, A.F. Dulhunty, and R.T. Dirksen. (2007). Triadin binding to the C-terminal luminal loop of the ryanodine receptor is important for skeletal muscle excitation contraction coupling. J Gen Physiol 130: 365-378. 17846166
Le Scouarnec, S., N. Bhasin, C. Vieyres, T.J. Hund, S.R. Cunha, O. Koval, C. Marionneau, B. Chen, Y. Wu, S. Demolombe, L.S. Song, H. Le Marec, V. Probst, J.J. Schott, M.E. Anderson, and P.J. Mohler. (2008). Dysfunction in ankyrin-B-dependent ion channel and transporter targeting causes human sinus node disease. Proc. Natl. Acad. Sci. USA 105: 15617-15622. 18832177
Li, Z.P., E.P. Burke, J.S. Frank, V. Bennett, and K.D. Philipson. (1993). The cardiac Na+-Ca2+ exchanger binds to the cytoskeletal protein ankyrin. J. Biol. Chem. 268: 11489-11491. 8505285
Liao, Y.H., S.M. Hsu, and P.H. Huang. (2007). ARMS depletion facilitates UV irradiation induced apoptotic cell death in melanoma. Cancer Res 67: 11547-11556. 18089783
Liu, X., Z. Spicarová, S. Rydholm, J. Li, H. Brismar, and A. Aperia. (2008). Ankyrin B modulates the function of Na,K-ATPase/inositol 1,4,5-trisphosphate receptor signaling microdomain. J. Biol. Chem. 283: 11461-11468. 18303017
Lu, H., D.N. Rate, J.T. Song, and J.T. Greenberg. (2003). ACD6, a novel ankyrin protein, is a regulator and an effector of salicylic acid signaling in the Arabidopsis defense response. Plant Cell 15: 2408-2420. 14507999
Lu, H., S. Salimian, E. Gamelin, G. Wang, J. Fedorowski, W. LaCourse, and J.T. Greenberg. (2009). Genetic analysis of acd6-1 reveals complex defense networks and leads to identification of novel defense genes in Arabidopsis. Plant J. 58: 401-412. 19144005
Lu, H., Y. Liu, and J.T. Greenberg. (2005). Structure-function analysis of the plasma membrane- localized Arabidopsis defense component ACD6. Plant J. 44: 798-809. 16297071
Mack, K. and M.J.M. Fischer. (2017). Disrupting sensitization of TRPV4. Neuroscience 352: 1-8. [Epub: Ahead of Print] 28372987
Marty, I. (2015). Triadin regulation of the ryanodine receptor complex. J. Physiol. 593: 3261-3266. 26228554
Miura, K. and M. Ohta. (2010). SIZ1, a small ubiquitin-related modifier ligase, controls cold signaling through regulation of salicylic acid accumulation. J Plant Physiol. 167: 555-560. 19959255
Mohler, P.J., J.J. Schott, A.O. Gramolini, K.W. Dilly, S. Guatimosim, W.H. duBell, L.S. Song, K. Haurogne, F. Kyndt, M.E. Ali, T.B. Rogers, W.J. Lederer, D. Escande, H. Le Marec, and V. Bennett. (2003). Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death. Nature 421: 634-639. 12571597
Mohler, P.J., J.Q. Davis, and V. Bennett. (2005). Ankyrin-B coordinates the Na/K ATPase, Na/Ca exchanger, and InsP3 receptor in a cardiac T-tubule/SR microdomain. PLoS Biol. 3: e423. 16292983
Rao, P.V. and R. Maddala. (2016). Ankyrin-B in lens architecture and biomechanics: Just not tethering but more. Bioarchitecture 6: 39-45. 27044909
Roux-Buisson, N., M. Cacheux, A. Fourest-Lieuvin, J. Fauconnier, J. Brocard, I. Denjoy, P. Durand, P. Guicheney, F. Kyndt, A. Leenhardt, H. Le Marec, V. Lucet, P. Mabo, V. Probst, N. Monnier, P.F. Ray, E. Santoni, P. Trémeaux, A. Lacampagne, J. Fauré, J. Lunardi, and I. Marty. (2012). Absence of triadin, a protein of the calcium release complex, is responsible for cardiac arrhythmia with sudden death in human. Hum Mol Genet 21: 2759-2767. 22422768
Sébastien, M., P. Aubin, J. Brocard, J. Brocard, I. Marty, and J. Fauré. (2020). Dynamics of triadin, a muscle-specific triad protein, within sarcoplasmic reticulum subdomains. Mol. Biol. Cell 31: 261-272. 31877066
Shcheglovitov, A., O. Shcheglovitova, M. Yazawa, T. Portmann, R. Shu, V. Sebastiano, A. Krawisz, W. Froehlich, J.A. Bernstein, J.F. Hallmayer, and R.E. Dolmetsch. (2013). SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients. Nature 503: 267-271. 24132240
Srikanth, S., M. Jew, K.D. Kim, M.K. Yee, J. Abramson, and Y. Gwack. (2012). Junctate is a Ca2+-sensing structural component of Orai1 and stromal interaction molecule 1 (STIM1). Proc. Natl. Acad. Sci. USA 109: 8682-8687. 22586105
Zhang, Z., J. Shrestha, C. Tateda, and J.T. Greenberg. (2014). Salicylic acid signaling controls the maturation and localization of the arabidopsis defense protein ACCELERATED CELL DEATH6. Mol Plant 7: 1365-1383. 24923602