SPTAN1 explained

Alpha II-spectrin, also known as Spectrin alpha chain, brain is a protein that in humans is encoded by the SPTAN1 gene.^{[1] [2] [3]} Alpha II-spectrin is expressed in a variety of tissues, and is highly expressed in cardiac muscle at Z-disc structures, costameres and at the sarcolemma membrane. Mutations in alpha II-spectrin have been associated with early infantile epileptic encephalopathy-5, and alpha II-spectrin may be a valuable biomarker for Guillain–Barré syndrome and infantile congenital heart disease.

Structure

Alternate splicing of alpha II-spectrin has been documented and results in multiple transcript variants; specifically, cardiomyocytes have four identified alpha II-spectrin splice variants.^{[4] [5]} As opposed to alpha I-spectrin that is principally found in erythrocytes,^[6] alpha II-spectrin is expressed in most tissues. In cardiac tissue, alpha II-spectrin is found in myocytes at Z-discs, costameres, and the sarcolemma membrane,^{[7] [8] [9]} and in cardiac fibroblasts along the surface of the cytoskeletal network.^[10] Alpha II-spectrin most commonly exists in a heterodimer with alpha II and beta II spectrin subunits; and dimers typically self-associate and heterotetramerize.^{[1] [11] [12]}

Function

The spectrins are a family of widely distributed cytoskeletal proteins which are involved in actin crosslinking, cell adhesion, intercellular communication and cell cycle regulation.^{[13] [14] [15]} Though a role in cardiac muscle is not well understood, it is likely that alpha II-spectrin is involved in organizing sub-sarcolemmal domains and stabilizing sarcolemmal membranes against the stresses associated with continuous cardiac contraction.^[12] Functional diversity of alpha II-spectrin is manifest through its four splice variants. First, a cardiac-specific, 21 amino acid sequence insert in the 21st spectrin repeat, termed alpha II-cardi+, was identified as an insert that modulates affinity of alpha II-spectrin for binding beta-spectrins and regulates myocyte growth and differentiation.^[4] Secondly, another insert of 20 amino acids in the 10th spectrin repeat, termed SH3i+, contains protein kinase A and protein kinase C phosphorylation sites and modulates Ca2+-dependent cleavage of spectrin and protein-protein interaction properties.^[16] Thirdly, an insert of five amino acids in the fifteenth spectrin motif bears a highly antigenic epitope resembling an ankyrin-like p53 binding protein binding site.^{[4] [17]} Fourthly, a six amino acid insert in the twenty-first spectrin motif with unknown function has been reported.^{[7] [18]}

Alpha II-spectrin gene expression has been shown to be upregulated in cardiac fibroblasts in response to Angiotensin II-induced cardiac remodeling.^[19]

In animal models of disease and injury, alpha II-spectrin has been implicated in diverse functions. In a canine model of hypothermic circulatory arrest, alpha II-spectrin breakdown products have shown to be relevant markers of neurologic injury post-cardiac surgery.^[20]

Clinical significance

Mutations in SPTAN1 are the cause of early infantile epileptic encephalopathy-5.^[21]

Alpha II-spectrin has shown promising utility as a biomarker for brain necrosis and apoptosis in infants with congenital heart disease; breakdown products of alpha II-spectrin have been detected in the serum of neonates in the perioperative period and following open-heart surgery.^[22] Elevated protein expression of alpha II-spectrin has been detected in cerebrospinal fluid in patients with Guillain–Barré syndrome.^[23]

Interactions

SPTAN1 has been shown to interact with:

• Abl gene,^[24]
• FANCA,^[25]
• Fanconi anemia, complementation group C,^{[26] [27]}
• GRIA2,^[28]
• Plectin,^[29]
• SHANK1,^[30] and
• Vimentin.^[31]

See also

• Sjögren's syndrome

Further reading

• Chow CW . Regulation and intracellular localization of the epithelial isoforms of the Na+/H+ exchangers NHE2 and NHE3. . Clinical and Investigative Medicine . 22 . 5 . 195–206 . 1999 . 10579058 .
• Hayashi Y, Arakaki R, Ishimaru N . The role of caspase cascade on the development of primary Sjögren's syndrome. . J. Med. Invest. . 50 . 1–2 . 32–8 . 2003 . 12630566 .
• Bennett V . Immunoreactive forms of human erythrocyte ankyrin are present in diverse cells and tissues. . Nature . 281 . 5732 . 597–9 . 1979 . 492324 . 10.1038/281597a0 . 1979Natur.281..597B . 263106 .
• Frappier T, Stetzkowski-Marden F, Pradel LA . Interaction domains of neurofilament light chain and brain spectrin. . Biochem. J. . (Pt 2) . 2. 521–7 . 1991 . 1902666 . 1150082 . 10.1042/bj2750521. 275 .
• Bennett AF, Hayes NV, Baines AJ . Site specificity in the interactions of synapsin 1 with tubulin. . Biochem. J. . (Pt 3) . 3. 793–9 . 1991 . 1905928 . 1151074 . 10.1042/bj2760793. 276 .
• Davis LH, Bennett V . Mapping the binding sites of human erythrocyte ankyrin for the anion exchanger and spectrin. . J. Biol. Chem. . 265 . 18 . 10589–96 . 1990 . 10.1016/S0021-9258(18)86987-3 . 2141335 . free .
• Moon RT, McMahon AP . Generation of diversity in nonerythroid spectrins. Multiple polypeptides are predicted by sequence analysis of cDNAs encompassing the coding region of human nonerythroid alpha-spectrin. . J. Biol. Chem. . 265 . 8 . 4427–33 . 1990 . 10.1016/S0021-9258(19)39582-1 . 2307671 . free .
• Langley RC, Cohen CM . Association of spectrin with desmin intermediate filaments. . J. Cell. Biochem. . 30 . 2 . 101–9 . 1986 . 2939097 . 10.1002/jcb.240300202 . 25080821 .
• Cianci CD, Giorgi M, Morrow JS . Phosphorylation of ankyrin down-regulates its cooperative interaction with spectrin and protein 3. . J. Cell. Biochem. . 37 . 3 . 301–15 . 1988 . 2970468 . 10.1002/jcb.240370305 . 42349239 .
• Steiner JP, Bennett V . Ankyrin-independent membrane protein-binding sites for brain and erythrocyte spectrin. . J. Biol. Chem. . 263 . 28 . 14417–25 . 1988 . 10.1016/S0021-9258(18)68236-5 . 2971657 . free .
• Herrmann H, Wiche G . Plectin and IFAP-300K are homologous proteins binding to microtubule-associated proteins 1 and 2 and to the 240-kilodalton subunit of spectrin. . J. Biol. Chem. . 262 . 3 . 1320–5 . 1987 . 10.1016/S0021-9258(19)75789-5 . 3027087 . free .
• McMahon AP, Giebelhaus DH, Champion JE, Bailes JA, Lacey S, Carritt B, Henchman SK, Moon RT . cDNA cloning, sequencing and chromosome mapping of a non-erythroid spectrin, human alpha-fodrin. . Differentiation . 34 . 1 . 68–78 . 1987 . 3038643 . 10.1111/j.1432-0436.1987.tb00052.x .
• Frappier T, Regnouf F, Pradel LA . Binding of brain spectrin to the 70-kDa neurofilament subunit protein. . Eur. J. Biochem. . 169 . 3 . 651–7 . 1988 . 3121319 . 10.1111/j.1432-1033.1987.tb13657.x . free .
• McMahon AP, Moon RT . Structure and evolution of a non-erythroid spectrin, human alpha-fodrin. . Biochem. Soc. Trans. . 15 . 5 . 804–7 . 1988 . 3691949 . 10.1042/bst0150804.
• Lundberg S, Björk J, Löfvenberg L, Backman L . Cloning, expression and characterization of two putative calcium-binding sites in human non-erythroid alpha-spectrin. . Eur. J. Biochem. . 230 . 2 . 658–65 . 1995 . 7607240 . 10.1111/j.1432-1033.1995.0658h.x . free .
• Hughes CA, Bennett V . Adducin: a physical model with implications for function in assembly of spectrin-actin complexes. . J. Biol. Chem. . 270 . 32 . 18990–6 . 1995 . 7642559 . 10.1074/jbc.270.32.18990 . free .
• Gregorio CC, Repasky EA, Fowler VM, Black JD . Dynamic properties of ankyrin in T lymphocytes: colocalization with spectrin and protein kinase C beta. . J. Cell Biol. . 125 . 2 . 345–58 . 1994 . 8163551 . 2120020 . 10.1083/jcb.125.2.345 .
• Li X, Bennett V . Identification of the spectrin subunit and domains required for formation of spectrin/adducin/actin complexes. . J. Biol. Chem. . 271 . 26 . 15695–702 . 1996 . 8663089 . 10.1074/jbc.271.26.15695 . free .
• Stabach PR, Cianci CD, Glantz SB, Zhang Z, Morrow JS . Site-directed mutagenesis of alpha II spectrin at codon 1175 modulates its mu-calpain susceptibility. . Biochemistry . 36 . 1 . 57–65 . 1997 . 8993318 . 10.1021/bi962034i .

Notes and References

1. Leto TL, Fortugno-Erikson D, Barton D, Yang-Feng TL, Francke U, Harris AS, Morrow JS, Marchesi VT, Benz EJ . Comparison of nonerythroid alpha-spectrin genes reveals strict homology among diverse species . Mol Cell Biol . 8 . 1 . 1–9 . February 1988 . 3336352 . 363070 . 10.1128/MCB.8.1.1.
2. Entrez Gene: SPTAN1 spectrin, alpha, non-erythrocytic 1 (alpha-fodrin). Molecular and Cellular Biology . 8 . 1 . 1–9 . 10.1128/MCB.8.1.1 . 3336352 . 363070 . 1988 . Leto . T. L. . Fortugno-Erikson . D. . Barton . D. . Yang-Feng . T. L. . Francke . U. . Harris . A. S. . Morrow . J. S. . Marchesi . V. T. . Benz . E. J. .
3. McMahon AP, Giebelhaus DH, Champion JE, Bailes JA, Lacey S, Carritt B, Henchman SK, Moon RT . cDNA cloning, sequencing and chromosome mapping of a non-erythroid spectrin, human alpha-fodrin . Differentiation . 34 . 1 . 68–78 . 1987 . 3038643 . 10.1111/j.1432-0436.1987.tb00052.x .
4. Zhang Y, Resneck WG, Lee PC, Randall WR, Bloch RJ, Ursitti JA . Characterization and expression of a heart-selective alternatively spliced variant of alpha II-spectrin, cardi+, during development in the rat . Journal of Molecular and Cellular Cardiology . 48 . 6 . 1050–9 . Jun 2010 . 20114050 . 10.1016/j.yjmcc.2010.01.001 . 3537504.
5. Cianci CD, Zhang Z, Pradhan D, Morrow JS . Brain and muscle express a unique alternative transcript of alphaII spectrin . Biochemistry . 38 . 48 . 15721–30 . Nov 1999 . 10625438 . 10.1021/bi991458k.
6. Ursitti JA, Kotula L, DeSilva TM, Curtis PJ, Speicher DW . Mapping the human erythrocyte beta-spectrin dimer initiation site using recombinant peptides and correlation of its phasing with the alpha-actinin dimer site . The Journal of Biological Chemistry . 271 . 12 . 6636–44 . Mar 1996 . 8636080 . 10.1074/jbc.271.12.6636 . free .
7. Du A, Sanger JM, Sanger JW . Cardiac myofibrillogenesis inside intact embryonic hearts . Developmental Biology . 318 . 2 . 236–46 . Jun 2008 . 18455713 . 10.1016/j.ydbio.2008.03.011 . 2496890.
8. Bennett PM, Maggs AM, Baines AJ, Pinder JC . The transitional junction: a new functional subcellular domain at the intercalated disc . Molecular Biology of the Cell . 17 . 4 . 2091–100 . Apr 2006 . 16481394 . 10.1091/mbc.E05-12-1109 . 1415289.
9. Bennett PM, Baines AJ, Lecomte MC, Maggs AM, Pinder JC . Not just a plasma membrane protein: in cardiac muscle cells alpha-II spectrin also shows a close association with myofibrils . Journal of Muscle Research and Cell Motility . 25 . 2 . 119–26 . 2004 . 15360127 . 10.1023/b:jure.0000035892.77399.51. 10297147 .
10. Sormunen R . Alpha-spectrin in detergent-extracted whole-mount cytoskeletons of chicken embryo heart fibroblasts . The Histochemical Journal . 25 . 9 . 678–86 . Sep 1993 . 8226104 . 10.1007/bf00157882. 34132236 .
11. Bignone PA, Baines AJ . Spectrin alpha II and beta II isoforms interact with high affinity at the tetramerization site . The Biochemical Journal . 374 . Pt 3 . 613–24 . Sep 2003 . 12820899 . 10.1042/BJ20030507 . 1223645.
12. Baines AJ, Pinder JC . The spectrin-associated cytoskeleton in mammalian heart . Frontiers in Bioscience . 10 . 1–3 . 3020–33 . 1 September 2005 . 15970557 . 10.2741/1759. free .
13. Ursitti JA, Petrich BG, Lee PC, Resneck WG, Ye X, Yang J, Randall WR, Bloch RJ, Wang Y . Role of an alternatively spliced form of alphaII-spectrin in localization of connexin 43 in cardiomyocytes and regulation by stress-activated protein kinase . Journal of Molecular and Cellular Cardiology . 42 . 3 . 572–81 . Mar 2007 . 17276456 . 10.1016/j.yjmcc.2006.11.018 . 1983066.
14. Metral S, Machnicka B, Bigot S, Colin Y, Dhermy D, Lecomte MC . AlphaII-spectrin is critical for cell adhesion and cell cycle . The Journal of Biological Chemistry . 284 . 4 . 2409–18 . Jan 2009 . 18978357 . 10.1074/jbc.M801324200 . 18821519 . free .
15. Sridharan DM, McMahon LW, Lambert MW . alphaII-Spectrin interacts with five groups of functionally important proteins in the nucleus . Cell Biology International . 30 . 11 . 866–78 . Nov 2006 . 16889989 . 10.1016/j.cellbi.2006.06.005 . 28863657 .
16. Nedrelow JH, Cianci CD, Morrow JS . c-Src binds alpha II spectrin's Src homology 3 (SH3) domain and blocks calpain susceptibility by phosphorylating Tyr1176 . The Journal of Biological Chemistry . 278 . 9 . 7735–41 . Feb 2003 . 12446661 . 10.1074/jbc.M210988200 . free .
17. Kennedy SP, Warren SL, Forget BG, Morrow JS . Ankyrin binds to the 15th repetitive unit of erythroid and nonerythroid beta-spectrin . The Journal of Cell Biology . 115 . 1 . 267–77 . Oct 1991 . 1833409 . 10.1083/jcb.115.1.267 . 2289929.
18. Moorthy S, Chen L, Bennett V . Caenorhabditis elegans beta-G spectrin is dispensable for establishment of epithelial polarity, but essential for muscular and neuronal function . The Journal of Cell Biology . 149 . 4 . 915–30 . May 2000 . 10811831 . 10.1083/jcb.149.4.915 . 2174577.
19. Wang XF, Gao GD, Liu J, Guo R, Lin YX, Chu YL, Han FC, Zhang WH, Bai YJ . Identification of differentially expressed genes induced by angiotensin II in rat cardiac fibroblasts . Clinical and Experimental Pharmacology & Physiology . 33 . 1–2 . 41–6 . 2006 . 16445697 . 10.1111/j.1440-1681.2006.04321.x . 21008341 . free .
20. Weiss ES, Wang KK, Allen JG, Blue ME, Nwakanma LU, Liu MC, Lange MS, Berrong J, Wilson MA, Gott VL, Troncoso JC, Hayes RL, Johnston MV, Baumgartner WA . Alpha II-spectrin breakdown products serve as novel markers of brain injury severity in a canine model of hypothermic circulatory arrest . The Annals of Thoracic Surgery . 88 . 2 . 543–50 . Aug 2009 . 19632410 . 10.1016/j.athoracsur.2009.04.016 . 3412404.
21. Writzl K, Primec ZR, Stražišar BG, Osredkar D, Pečarič-Meglič N, Kranjc BS, Nishiyama K, Matsumoto N, Saitsu H . Early onset West syndrome with severe hypomyelination and coloboma-like optic discs in a girl with SPTAN1 mutation . Epilepsia . 53 . 6 . e106–10 . Jun 2012 . 22429196 . 10.1111/j.1528-1167.2012.03437.x . 20216273 .
22. Jain P, Spaeder MC, Donofrio MT, Sinha P, Jonas RA, Levy RJ . Detection of alpha II-spectrin breakdown products in the serum of neonates with congenital heart disease* . Pediatric Critical Care Medicine . 15 . 3 . 229–35 . Mar 2014 . 24395002 . 10.1097/PCC.0000000000000059 . 4059536.
23. Lehmensiek V, Süssmuth SD, Brettschneider J, Tauscher G, Felk S, Gillardon F, Tumani H . Proteome analysis of cerebrospinal fluid in Guillain–Barré syndrome (GBS) . Journal of Neuroimmunology . 185 . 1–2 . 190–4 . Apr 2007 . 17367871 . 10.1016/j.jneuroim.2007.01.022 . 28987593 .
24. Ziemnicka-Kotula D, Xu J, Gu H, Potempska A, Kim KS, Jenkins EC, Trenkner E, Kotula L . Identification of a candidate human spectrin Src homology 3 domain-binding protein suggests a general mechanism of association of tyrosine kinases with the spectrin-based membrane skeleton . J. Biol. Chem. . 273 . 22 . 13681–92 . May 1998 . 9593709 . 10.1074/jbc.273.22.13681. free .
25. Sridharan D, Brown M, Lambert WC, McMahon LW, Lambert MW . Nonerythroid alphaII spectrin is required for recruitment of FANCA and XPF to nuclear foci induced by DNA interstrand cross-links . J. Cell Sci. . 116 . Pt 5 . 823–35 . March 2003 . 12571280 . 10.1242/jcs.00294. free .
26. McMahon LW, Sangerman J, Goodman SR, Kumaresan K, Lambert MW . Human alpha spectrin II and the FANCA, FANCC, and FANCG proteins bind to DNA containing psoralen interstrand cross-links . Biochemistry . 40 . 24 . 7025–34 . June 2001 . 11401546 . 10.1021/bi002917g.
27. McMahon LW, Walsh CE, Lambert MW . Human alpha spectrin II and the Fanconi anemia proteins FANCA and FANCC interact to form a nuclear complex . J. Biol. Chem. . 274 . 46 . 32904–8 . November 1999 . 10551855 . 10.1074/jbc.274.46.32904. free .
28. Hirai H, Matsuda S . Interaction of the C-terminal domain of delta glutamate receptor with spectrin in the dendritic spines of cultured Purkinje cells . Neurosci. Res. . 34 . 4 . 281–7 . September 1999 . 10576550 . 10.1016/s0168-0102(99)00061-9. 45794233 .
29. Herrmann H, Wiche G . Plectin and IFAP-300K are homologous proteins binding to microtubule-associated proteins 1 and 2 and to the 240-kilodalton subunit of spectrin . J. Biol. Chem. . 262 . 3 . 1320–5 . January 1987 . 10.1016/S0021-9258(19)75789-5 . 3027087 . free .
30. Böckers TM, Mameza MG, Kreutz MR, Bockmann J, Weise C, Buck F, Richter D, Gundelfinger ED, Kreienkamp HJ . Synaptic scaffolding proteins in rat brain. Ankyrin repeats of the multidomain Shank protein family interact with the cytoskeletal protein alpha-fodrin . J. Biol. Chem. . 276 . 43 . 40104–12 . October 2001 . 11509555 . 10.1074/jbc.M102454200 . free .
31. Brown MJ, Hallam JA, Liu Y, Yamada KM, Shaw S . Cutting edge: integration of human T lymphocyte cytoskeleton by the cytolinker plectin . J. Immunol. . 167 . 2 . 641–5 . July 2001 . 11441066 . 10.4049/jimmunol.167.2.641. free .