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).
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