Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Alpha-1-Syntrophin

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101491

Synonyms

Historical Background

Syntrophins were first identified in the postsynaptic membranes of the Torpedo electric organ. Alpha-1-syntrophin is a 58 kDa peripheral cytoplasmic membrane adaptor protein and is a member of the syntrophin family. It is encoded by the SNTA gene in humans and is 505 amino acids long. The full-length cDNA is 2,163 bp long. It encodes a single large open reading frame which maps to chromosome 20q11.2 (Adams et al. 1993, 1995; Ahn et al. 1994; Yang et al. 1994). The human alpha-1-syntrophin is 94% identical to the mouse sequence and about 93% identical to the rabbit sequence (Ahn et al. 1994, 1996a). Alpha-1-syntrophin is the acidic isoform (pI = 6.7) of the syntrophin family. It was the first isoform of the syntrophin to be discovered (Adams et al. 1995; Froehner et al. 1997) and has since been cloned and characterized (Ahn et al. 1996a). Alpha-1-syntrophin exists as a monomer as well as a dimer in the cell. Alpha-1-syntrophin is expressed in skeletal muscles (Ahn et al. 1996a) and mammalian tissues like heart, brain, stomach, breasts, etc. It forms a part of the dystrophin glycoprotein complex (DGC) in muscle cells or is concentrated at the neuromuscular junction in the brain.

Alpha-1-Syntrophin Structure

All members of the syntrophin family share a common domain organization. Alpha-1-syntrophin has two PH-domains viz. one N-terminal split PH1 domain and one central PH2 domain. Alpha-1-syntrophin also has a C-terminal Syntrophin Unique (SU) domain. The first PH domain (PH1) is interrupted by a PDZ domain. This structure of PH1 domain split by PDZ domain is quite unique. The N-terminal PH1 extends from amino acid number 1–77. The C-terminal half of PH1 domain extends from amino acid number 162–271. The embedded PDZ domain lies between these two halves and is 80 amino acid long. The N-terminal PH1 domain is composed of three β-strands and the C-terminal of PH1 is composed of four β-strands. The PDZ domain is composed of seven β-strands and two α-helices. The PH2 domain of alpha-1-syntrophin extends from amino acid number 281–406. The PH2 domain is composed of two β-strands with one end of the barrel capped with a C-terminal α-helix. The 57 amino acids towards the C-terminal exhibit strong homology among all the isoforms of the syntrophin family. This is the syntrophin unique (SU) domain and consists three to five β-strands (Adams et al. 1993; Ahn et al. 1994, 1996a; Yang et al. 1994). The split PH domain and the SU domain are responsible for the interactions between the DGC and alpha-1-syntrophin (Ahn et al. 1994; Adams et al. 1995). All these domains of alpha-1-syntrophin play a role in various signal transduction mechanisms as well as cytoskeletal dynamics (Fig. 1).
Alpha-1-Syntrophin, Fig. 1

Alpha-1-syntrophin domain organization

Alpha-1-Syntrophin and Cell Signaling

The split PH1 domain and the SU domain are involved in interactions between alpha-1-syntrophin and the DGC. These domains allow alpha-1-syntrophins to interact with several proteins, glycoproteins, lipids, receptors, etc., and to play a key role in linking several cell components to the DGC and, therefore, regulate many downstream signaling pathways.

The PH1 domain of alpha-1-syntrophin binds phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2). The N-terminal of the PH1 domain and the N-terminal of the PDZ domain have been reported to bind calmodulin and PH1 binds calcium as well. The binding of Ca2+-calmodulin to alpha-1-syntrophin inhibits the syntrophin-dystrophin interaction. Alpha-1-syntrophin has been shown to play an important role in the G-protein signaling mechanisms. The interaction between G-proteins and alpha-1-syntrophin is well established. The binding of G-proteins to the PDZ domain of alpha-1-syntrophin is induced by laminin α1. The binding of laminin to α-dystroglycan of the DGC causes the trimeric G-proteins and the PDZ domain of alpha-1-syntrophin to associate. The PDZ domain of alpha-1-syntrophin binds to the heterotrimeric G protein, Gβγ, sequestering the G-proteins into their inactive form. This leads to Gα subunit being unable to bind Ca2+ channels, which in turn leads to a drastic decrease in the Ca2+ levels in the cell. Gα subunit of G-proteins binds to alpha-1-syntrophin. This binding occurs via the PH1 domain and the SU domain. The PDZ domain of alpha-1-syntrophin binds voltage-gated Na+-channels in muscles and nerves (Oak et al. 2001, 2003) (Fig. 2).
Alpha-1-Syntrophin, Fig. 2

Alpha-1-syntrophin structure and interactions mediated by its different domains in the cell

Alpha-1-syntrophin also binds stress-activated protein kinase 3 (SAPK3) (Hasegawa et al. 1999). This binding occurs via the KETXL sequence on the C-terminal of the PDZ domain. SAPK3 phosphorylates alpha-1-syntrophin on serine-193 and serine-201 residues. In skeletal muscle cells, Neuronal nitric oxide synthase (nNOS) has been shown to bind to alpha-1-syntrophin, localizing it to the sarcolemma via the DGC. The sarcolemmal calcium pump, nNOS and alpha-1-syntrophin form a ternary complex with each other. The PDZ domain of nNOS binds to the PDZ domain of alpha-1-syntrophin. Grb2 binds to alpha-1-syntrophin via its SH2 domain when alpha-1-syntrophin is phosphorylated on a tyrosine residue. This binding of Grb2 to the phosphorylated alpha-1-syntrophin allows Grb2 to activate Son of Sevenless (Sos1) protein. The activated Sos1 protein in turn activates Rac1 protein and the rest of the signaling pathway. Unphosphorylated alpha-1-syntrophin binds to the C-terminal SH3 domain of Grb2 (Madhavan et al. 1992; Oak et al. 2001, 2003; Bhat et al. 2014). The signaling pathway via the DGC links the matrix laminin binding on the outside of the sarcolemma to the DGC on the inside. This signaling pathway has been described as alpha-1-syntrophin-Grb2-Sos1-Rac1-PAK1-JNK followed by the phosphorylation of c-jun on S65 and the rest of the pathway. The binding of laminin induces a conformational change in alpha-1-syntrophin, which in turn leads to its phosphorylation of a tyrosine residue. This phosphorylation is crucial for its binding to Grb2 and activation of Sos1 and Rac1.

Alpha-1-syntrophin has been shown to be overexpressed in breast cancer tissues as compared to the adjacent normal (Bhat et al. 2011). Differential expression of alpha-1-syntrophin has also been observed in colon cancer and esophageal squamous cell carcinoma (Fig. 3).
Alpha-1-Syntrophin, Fig. 3

Alpha-1-syntrophin and the various pathologies mediated by it

Alpha-1-Syntrophin and the Cytoskeleton

Through its association with the DGC, alpha-1-syntrophin has been shown to act as the link between the extracellular matrix, the internal cell signaling apparatus, and the actin cytoskeleton (Adams et al. 2000).

It has been seen that actin depolymerization leads to a reduction in the tyrosine phosphorylation of alpha-1-syntrophin as well as a reduction in the interaction between alpha-1-syntrophin and Rac1 protein in breast carcinoma cells. This actin depolymerization mediated loss of tyrosine phosphorylation of alpha-1-syntrophin further leads to a loss of Rac1 activation and an increase in cell apoptosis, a decrease in cell migration, and a decrease in intracellular ROS production in breast carcinoma cells (Bhat et al. 2016).

In muscle cells, dystrophin glycoprotein complex (DGC) has been implicated in the modulation of the actin cytoskeleton at the membrane (Petrof et al. 1993; Abramovici et al. 2003; Hogan et al. 2004). Alpha-1-syntrophin has been shown to play an important role in executing this function of the DGC. Alpha-1-syntrophin has been shown to bind actin via the PH2 domain and the C-terminal SU domain. Many lipid proteins, such as phosphoinositol-3-kinase (PI3K) and diacylglycerol-ξ (DGK-ξ), have been shown to bind alpha-1-syntrophin. These lipid molecules are implicated in the actin remodeling and cytoskeletal dynamism. Phosphoinositol-3,4-bisphosphate (PI(3,4)P2) and phosphoinositol-3,4,5-trisphosphate (PI(3,4,5)P3) are produced upon growth factor stimulation and bring about changes in actin organization. These signaling phosphoinositides recruit PH-domain containing protein to the sites of receptor activation at the plasma membrane (Hogan et al. 2004). TAPP1 (tandem PH domain containing proteins1) is one of the PH-domain containing proteins recruited to the plasma membrane under these conditions. When these signaling proteins are activated they lead to actin reorganization among other effects. At the plasma membrane, both TAPP1 and (PI(3,4)P2) get activated and bring about responses like actin cytoskeleton reorganization. TAPP1 has been shown to bind to the PDZ domain of alpha-1-syntrophin via its C-terminal PDZ domain. This points to the role of alpha-1-syntrophin in actin cytoskeleton organization (Dowler et al. 1999; Marshall et al. 2002) (Fig. 4).
Alpha-1-Syntrophin, Fig. 4

Various functional implications brought about by alpha-1-syntrophin in the cell

Summary

Alpha-1-syntrophin is a membrane associated protein of the syntrophin family. The domain organization of alpha-1-syntrophin is PH1, PDZ, PH2, and SU domains. It is via these domains that alpha-1-syntrophin functions as an adaptor protein and binds various signaling molecules. Alpha-1-syntrophin is expressed in skeletal muscles and mammalian tissues like heart, brain, stomach, breasts, etc. It forms a part of the dystrophin glycoprotein complex (DGC) in muscle cells and via the DGC forms a part of cell signaling pathways. Alpha-1-syntrophin has been shown to be involved in cytoskeleton organization via its interaction with TAPP1 protein. It also binds actin via PH2 and SU domain. Alpha-1-syntrophin also plays a role in the regulation of ROS generation, Rac1 activation, cell proliferation, apoptosis, and cell migration. By mediating these processes, alpha-1-syntrophin is fast emerging as a regulator of carcinogenesis and can possibly be used as a therapeutic target aimed at preventing pathologies like cancer in the future.

References

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of BiotechnologyUniversity of KashmirSrinagarIndia