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
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).
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.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).
Interaction of Gamma-1-Syntrophin with Other Proteins
Physiological Functions of Gamma-1-Syntrophin
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.
- 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
- 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
- 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