Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Gamma-1-Syntrophin

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101492

Synonyms

Historical Background Putative

Gamma syntrophins were discovered by a team of scientists led by Giulio Pilusoin in the year 2000. They found that human neuronal cell contains two novel proteins which have domain organization similar to already discovered syntrophins. They named these two proteins as gamma-1-syntrophin (SNTG1) and gamma-2-syntrophin (SNTG2). Syntrophins are adapter proteins which include other three known homologous isoforms alpha-1-syntrophin (SNTA1), beta-1-syntrophin (SNTB1), and beta-2-syntrophin (SNTB2) (Froehner et al. 1997). Syntrophins are usually found associated with dystrophin family of proteins and got their name from a Greek word “syntrophos” meaning “companion” or “associate” (Froehner et al. 1997). Gamma-1-syntrophin protein is encoded by SNTG1 gene which is located on chromosome 1 in mouse and on chromosome 8 in humans. Human SNTG1 gene is composed of 19 exons and codes for a brain-specific protein of 517 amino acids (Piluso et al. 2000). Mouse SNTG1 shares extensive homology with the human SNTG1. The protein in mouse and human shows a difference of only 37 amino acids and out of which 20 amino acids are conserved substitutions (Alessi et al. 2006). Like other members of syntrophin family SNTG1possess multiple protein-binding domains viz. PH1, PDZ, PH2, and SU and p-loop which simultaneously bind and localize its binding partners to specialized locations (Piluso et al. 2000). Each of the characterized syntrophins has a unique tissue distribution. SNTA1 is expressed at high levels in skeletal, breast and cardiac tissues and at low levels in brain and kidney (Ahn et al. 1996; Bhat et al. 2011). SNTB1 is expressed in skeletal and smooth muscles, liver, and kidney and is expressed at low levels in many other tissues. Highest levels of SNTB2 are found in testis, brain, liver, kidney, and intestinal smooth muscle with relatively low levels in skeletal muscle (Ahn et al. 1996). SNTG2 is widely expressed with the highest levels in liver. It is also present in testis, kidney, lung, brain, and heart (Piluso et al. 2000). SNTG1 is highly expressed in brain and very less is present in testis (Piluso et al. 2000; Alessi et al. 2006). In neuronal cells, SNTG1 is highly expressed in hippocampal pyramidal cells, cerebellar Purkinje neurons, and cortical neurons. In subcellular locations apart from being localized near cell membrane and cytosol, SNTG1 is also localized to the ER and in the nucleus (Alessi et al. 2006).

Structure of Gamma-1-Syntrophin

SNTG1 like other members of syntrophin family contains PDZ (postsynaptic density protein-95/disc large/zona occludens-1) which split PH1 (pleckstrin homology domain-1) into PH1a and PH1b, PH2 (pleckstrin homology domain-2), and a SU (syntrophin unique) domain (Fig. 1). In addition to these domains, SNTG1 and SNTG2 contain P-loop at C-terminus. SNTG1 shares around 50% amino acid identities with SNTG2 and 15–20% of amino acid homology with other three syntrophin members (Alessi et al. 2006) (Fig. 2). These two proteins could be considered as subgroup in the family of syntrophin proteins. The main differences between gamma-1-syntrophin and other syntrophins are:
  1. 1.

    The first PH domain of the SNTG1 does not fit the consensus sequence for PH domains as well as the corresponding sequence of the α- and β-syntrophins but does retain the key elements of a PH domain (Alessi et al. 2006).

     
  2. 2.

    The conserved elements include a charged amino acid at position 11 and at position 34. Also conserved are the hydrophobic residues at positions 17, 25, 29, 36, and 38. The second PH domain, the PDZ domain, and the SU domain of the SNTG1 all fit the consensus for the respective domains (Alessi et al. 2006).

     
  3. 3.
    SNTG1 has an extended C-terminal tail of about 23 amino acids that contains a P-loop, a potential nucleotide binding site. P-loops bind ATP or GTP and are often found in kinases and motor proteins (Alessi et al. 2006).
    Gamma-1-Syntrophin, Fig. 1

    Structure of gamma-1-syntrophin

    Gamma-1-Syntrophin, Fig. 2

    Percent amino acid identity between the five mouse syntrophins

     

Interaction of Gamma-1-Syntrophin with Other Proteins

SNTG1 possesses five different domains through which it interacts with different proteins to carry out different physiological functions. It differs from other syntrophins in preferred PDZ ligands and interactions with dystrophin family members. The PDZ domain of SNTG1 and SNTG2 does not bind to nNOS like other isoforms of these two proteins (Alessi et al. 2006). In vivo human gamma syntrophins interact with dystrophin protein (Piluso et al. 2000), whereas mouse isoform of these proteins does not bind to dystrophin or their interaction is weak or transient (Alessi et al. 2006). In case of SNTG1, P-loop mediates this interaction with dystrophin protein (Piluso et al. 2000). In in-vitro conditions, gamma syntrophins bind to dystrophin family but binding pattern is different. Each member of the dystrophin family has two closely spaced syntrophin-binding sites (SBS) via which they interact with dystrophin complex. Gamma syntrophins bind to only first syntrophin-binding sites (SBS) and not with the second, whereas all other syntrophins bind to both SBS domains. Gamma syntrophins bind to first SBS1 domain of dystrophin, utrophin, and DRP2, while as with α-dystrobrevin these proteins interact via SBS2 domain (Alessi et al. 2006). SNTG1 via its PDZ domain interacts with C-terminal motif of diacylglycerol kinase-zeta and has been proposed to regulate the activity of proteins like protein kinase C (Hogan et al. 2001). SNTG1 shows strong interaction with TAPP1 (tandem PH domain-containing proteins 1) as compared to its interaction with other isoforms of syntrophin family of proteins. This interaction is mediated via its PDZ domain with 10 amino acids C-terminal motif of TAPP1. It has been found that this interaction is stronger than with other isoforms of syntrophins (Hogan et al. 2004). Gamma-enolase which possesses neurotrophic activities also interacts with SNTG1 via its PDZ domain (Hafner et al. 2010) (Fig. 3).
Gamma-1-Syntrophin, Fig. 3

Diagrammatic representation of the various interactions shown by SNTG1

Physiological Functions of Gamma-1-Syntrophin

Gamma-1-syntrophin has been implicated in idiopathic scoliosis. Scoliosis is a prevalent abnormality of the vertebral column in which patients develop lateral curvature of the spine. By definition, this curvature is greater than 10° as measured by the Cobb method (Cobb 1948). It has been found in affected individual there is inversion on chromosome 8 or DNA is mutated or damaged where SNTG1 gene is located (Bashiardes et al. 2004). Diacylglycerol kinase-zeta regulates the activity of protein kinase C. DGK-ɀ converts diacylglycerol to phosphotidic acid and thus can attenuate the PKC signaling. Prolonged activation of this PKC leads to cell proliferation and malignant transformation. DGKɀ via its interaction with SNTG1 translocates it from cytosol to nucleus and regulates nuclear PKC by regulating nuclear DAG (Hogan et al. 2001). Gamma-1-syntrophin has been implicated in the regulation of cytoskeleton organization through its interaction with TAPP1 (Hogan et al. 2004). Growth factors like PDGF activates PI3 Kinase which recruits cytoskeletal organizing protein TAPP1 to the plasma membrane (Buccione et al. 2004). SNTG1 shows very strong interaction with the C-terminal motif of TAPP1 which suggests that this protein contributes to its intracellular location (Hogan et al. 2004). It is known that the C-terminal part of neuron-specific enolase has a neurotrophic activity when it is bound to the plasma membrane of neuronal cells. However, until recently the mechanism of its transport to the plasma membrane was not known. Now it has been demonstrated that gamma-1-syntrophin helps in its transport to the plasma membrane via its PDZ-domain interaction with the C-terminal motif of gamma enolase (Hafner et al. 2010) (Fig. 4).
Gamma-1-Syntrophin, Fig. 4

Functional implications of SNTG1

Summary

SNTG1 belongs to syntrophin family of adapter proteins that bind several signaling molecules and localize them to the membrane. SNTG1 is also localized to ER, cytosol, and nucleus. The four other known members of this protein family are SNTA1, SNTB1, SNTB2, and SNTG2. All the syntrophin have same domain organization viz. PH1, PDZ, PH2, and SU. SNTG1 and SNTG2 contain additional p-loop at C-terminus. Each of the characterized syntrophin has a unique tissue distribution. Gamma-1-syntrophin (SNTG1) is highly expressed in brain. SNTG1 plays an important role in the physiology of neuronal cells. Gamma-enolase that carries out neurotrophic function at the plasma membrane is translocated by SNTG1 from cytosol to the plasma membrane. SNTG1 also regulates PKC via interaction with diacylglycerol kinase-zeta. In idiopathic scoliosis, SNTG1 gene is usually mutated or damaged. SNTG1 has also been implicated in cytoskeleton organization via its interaction with TAPP1 protein. SNTG1 shows very strong interaction with TAPP1 than all the other known interacting proteins of TAPP1. This suggests its major role in cytoskeletal organization. TAPP1 is a PH domain-containing adapter protein that is recruited to the plasma membrane of cells in response to phosphoinositol 3-kinase (PI3K) activation stimulated by PDGF. This leads to rapid reorganization of the actin cytoskeleton, which gives rise to the plasma membrane specializations including peripheral and dorsal circular ruffles.

References

  1. Ahn AH, Freener CA, Gussoni E, Yoshida M, Ozawa E, Kunkel LM. The three human syntrophin genes are expressed in diverse tissues, have distinct chromosomal locations, and each bind to dystrophin and its relatives. J Biol Chem. 1996;271:2724–30.PubMedCrossRefGoogle Scholar
  2. Alessi A, Bragg AD, Percival JM, Yoo J, Albrecht DE, Froehner SC, et al. Gamma-Syntrophin scaffolding is spatially and functionally distinct from that of the alpha/beta syntrophins. Exp Cell Res. 2006;312:3084–95. doi: 10.1016/j.yexcr.2006.06.019.PubMedCrossRefPubMedCentralGoogle Scholar
  3. Bashiardes S, Veile R, Allen M, Wise CA, Dobbs M, Morcuende JA, et al. SNTG1, the gene encoding gamma1-syntrophin: a candidate gene for idiopathic scoliosis. Hum Genet. 2004;115:81–9. doi: 10.1007/s00439-004-1121-y.PubMedCrossRefPubMedCentralGoogle Scholar
  4. Bhat HF, Baba RA, Bashir M, Saeed S, Kirmani D, Wani MM, et al. Alpha-1-syntrophin protein is differentially expressed in human cancers. Biomarkers. 2011;16:31–6. doi: 10.3109/1354750x.2010.522731.PubMedCrossRefPubMedCentralGoogle Scholar
  5. Buccione R, Orth JD, McNiven MA. Foot and mouth: podosomes, invadopodia and circular dorsal ruffles. Nat Rev Mol Cell Biol. 2004;5:647–57. doi: 10.1038/nrm1436.PubMedCrossRefPubMedCentralGoogle Scholar
  6. Cobb J. Outline for the study of scoliosis. In: American Academy of Orthopaedic Surgeons, editors. Instructional course lectures. Ann Arbor 1948;5. p. 261–5.Google Scholar
  7. Froehner SC, Adams ME, Peters MF, Gee SH. Syntrophins: modular adapter proteins at the neuromuscular junction and the sarcolemma. Soc Gen Physiol Ser. 1997;52:197–207.PubMedPubMedCentralGoogle Scholar
  8. Hafner A, Obermajer N, Kos J. Gamma-1-syntrophin mediates trafficking of gamma-enolase towards the plasma membrane and enhances its neurotrophic activity. Neurosignals. 2010;18:246–58. doi: 10.1159/000324292.PubMedCrossRefPubMedCentralGoogle Scholar
  9. Hogan A, Shepherd L, Chabot J, Quenneville S, Prescott SM, Topham MK, et al. Interaction of gamma 1-syntrophin with diacylglycerol kinase-zeta. Regulation of nuclear localization by PDZ interactions. J Biol Chem. 2001;276:26526–33. doi: 10.1074/jbc.M104156200.PubMedCrossRefPubMedCentralGoogle Scholar
  10. Hogan A, Yakubchyk Y, Chabot J, Obagi C, Daher E, Maekawa K, et al. The phosphoinositol 3,4-bisphosphate-binding protein TAPP1 interacts with syntrophins and regulates actin cytoskeletal organization. J Biol Chem. 2004;279:53717–24. doi: 10.1074/jbc.M410654200.PubMedCrossRefPubMedCentralGoogle Scholar
  11. Piluso G, Mirabella M, Ricci E, Belsito A, Abbondanza C, Servidei S, et al. Gamma1- and gamma2-syntrophins, two novel dystrophin-binding proteins localized in neuronal cells. J Biol Chem. 2000;275:15851–60. doi: 10.1074/jbc.M000439200.PubMedCrossRefPubMedCentralGoogle Scholar

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of BiotechnologyUniversity of KashmirSrinagarIndia