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).

This family belongs to the Ankyrin Repeat Domain-containing (Ank) Family, found in at least some proteins in the following TC families .



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.

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.

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]

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.

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]

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.

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.

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.

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.

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.

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.

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.

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.

Mack, K. and M.J.M. Fischer. (2017). Disrupting sensitization of TRPV4. Neuroscience 352: 1-8. [Epub: Ahead of Print]

Marty, I. (2015). Triadin regulation of the ryanodine receptor complex. J. Physiol. 593: 3261-3266.

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.

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.

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.

Rao, P.V. and R. Maddala. (2016). Ankyrin-B in lens architecture and biomechanics: Just not tethering but more. Bioarchitecture 6: 39-45.

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.

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.

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.

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.


TC#NameOrganismal TypeExample

Ankyrin-B of 3924 aas and 1 N-terminal TMS.  Ankyrin-B plays roles in maintaining tissue cytoarchitecture, cell shape and biomechanical properties by promoting key protein:protein interactions required for membrane anchoring and organization of the spectrin-actin skeleton, scaffolding proteins and cell adhesive proteins (Rao and Maddala 2016).


Ankyrin-B of Homo sapiens (Q01484)


Ankyrin-1 of 1881 aas.  Small ankyrin 1 (sAnk1) is a 17-kDa transmembrane (TM) protein that binds to the cytoskeletal protein, obscurin, and stabilizes the network sarcoplasmic reticulum in skeletal muscle. It shares homology in its TM amino acid sequence with sarcolipin (TC# 1.A.50.2.1), a small protein inhibitor of the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA; TC# 3.A.3.2.7). sAnk1 and SERCA1 interact in their transmembrane domains to regulate SERCA (Desmond et al. 2015; Desmond et al. 2017).

Ankryn 1 of Homo sapiens


Triadin of 729 aas.  Contributes to the regulation of lumenal Ca2+ release via the sarcoplasmic reticulum calcium release channels RYR1 and RYR2, a key step in triggering skeletal and heart muscle contraction (Marty 2015). It is required for normal organization of the triad junction, where T-tubules and the sarcoplasmic reticulum terminal cisternae are in close contact. Triadin is required for normal skeletal muscle strength. It plays a role in excitation-contraction coupling in the heart and in regulating the rate of heart beats (Roux-Buisson et al. 2012). Triadin and junctin bind to different sites on RyR1; triadin plays an important role in ensuring rapid Ca2+ release during excitation-contraction coupling in skeletal muscle (Goonasekera et al. 2007).

Triadin of Homo sapiens


Junctin 2 of 245 aas and 1 TMS, a core component if the RyR1 complex (see TC#1.A.3.1.2).  Junctin, triadin and calsequestrin, are associated with the sarcopasmic reticulum in muscle cells. These SR proteins are not essential for survival but exert structural and functional influences that modify the gain of EC-coupling and maintain normal muscle function (Dulhunty et al. 2016).

Junctin of Mus musculus


Junctate, Junctin, Aspartate beta-hydroxylase, ASPH, BAH of 758 aas and 1 N-terminal TMS. It has enzyme activity, but is also a Ca2+-sensing ER protein, a structural component of ER-PM junctions where Orai1 and STIM1 cluster and interact in T cells (Srikanth et al. 2012). It plays a role in cardiac Ca2+ handeling (homeostatis), contractility and heart failure (Gergs et al. 2007).  Two other proteins of the complex are: Triadin and Calsequestrin.

Junctin of Homo sapiens


A-kinase anchor protein 5, AKAP5; AKAP79, of 427 aas. Associates with to the beta2-adrenergic receptor (beta2-AR) to regulate the beta2-AR signaling pathway.  Also binds directly to TrpV4 (TC# 1.A.4.2.5) (Mack and Fischer 2017).

AKAP5 of Homo sapiens


SH3 and multiple ankyrin repeat domains protein 3, SHANK3, or Proline-rich synapse-associated protein 2, PSAP2 or PROSAP2, of 1731 aas. It is a major scaffold postsynaptic density protein which interacts with multiple proteins and complexes. Interconnects receptors of the postsynaptic membrane including NMDA-type and metabotropic glutamate receptors via complexes with GKAP/PSD-95 and HOMER, respectively (Shcheglovitov et al. 2013).

SHANK3 of Homo sapiens


The accelerated cell death 6, ACD6, of 670 aas and 5 C-terminal TMSs. It is an activator of the defense response against virulent pathogens, including bacteria, fungi and oomycetes, that acts in a positive feedback loop with the defense signal salicylic acid (SA) (Lu et al. 2009).It regulates the salicylic acid (SA) signaling pathway leading to cell death and modulating cell fate (e.g. cell enlargement and/or cell division) (Lu et al. 2003). In response to SA signaling, it triggers the accumulation of FLS2 at the plasma membrane, thus priming defenses (Zhang et al. 2014). Irt it is involved in SA-dependent freezing signaling and tolerance (Miura and Ohta 2010). Information exchange between the ankyrin and transmembrane domains may be involved in activating defense signaling (Lu et al. 2005).


ACD6 of Arabidopsis thaliana