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]
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]
↑Cianci CD, Zhang Z, Pradhan D, Morrow JS (Nov 1999). "Brain and muscle express a unique alternative transcript of alphaII spectrin". Biochemistry. 38 (48): 15721–30. doi:10.1021/bi991458k. PMID10625438.
↑Ursitti JA, Kotula L, DeSilva TM, Curtis PJ, Speicher DW (Mar 1996). "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. PMID8636080.
↑Bennett PM, Baines AJ, Lecomte MC, Maggs AM, Pinder JC (2004). "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. doi:10.1023/b:jure.0000035892.77399.51. PMID15360127.
↑Sormunen R (Sep 1993). "Alpha-spectrin in detergent-extracted whole-mount cytoskeletons of chicken embryo heart fibroblasts". The Histochemical Journal. 25 (9): 678–86. doi:10.1007/bf00157882. PMID8226104.
↑Metral S, Machnicka B, Bigot S, Colin Y, Dhermy D, Lecomte MC (Jan 2009). "AlphaII-spectrin is critical for cell adhesion and cell cycle". The Journal of Biological Chemistry. 284 (4): 2409–18. doi:10.1074/jbc.M801324200. PMID18978357.
↑Sridharan DM, McMahon LW, Lambert MW (Nov 2006). "alphaII-Spectrin interacts with five groups of functionally important proteins in the nucleus". Cell Biology International. 30 (11): 866–78. doi:10.1016/j.cellbi.2006.06.005. PMID16889989.
↑Nedrelow JH, Cianci CD, Morrow JS (Feb 2003). "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. doi:10.1074/jbc.M210988200. PMID12446661.
↑Wang XF, Gao GD, Liu J, Guo R, Lin YX, Chu YL, Han FC, Zhang WH, Bai YJ (2006). "Identification of differentially expressed genes induced by angiotensin II in rat cardiac fibroblasts". Clinical and Experimental Pharmacology & Physiology. 33 (1–2): 41–6. doi:10.1111/j.1440-1681.2006.04321.x. PMID16445697.
↑Writzl K, Primec ZR, Stražišar BG, Osredkar D, Pečarič-Meglič N, Kranjc BS, Nishiyama K, Matsumoto N, Saitsu H (Jun 2012). "Early onset West syndrome with severe hypomyelination and coloboma-like optic discs in a girl with SPTAN1 mutation". Epilepsia. 53 (6): e106–10. doi:10.1111/j.1528-1167.2012.03437.x. PMID22429196.
↑Lehmensiek V, Süssmuth SD, Brettschneider J, Tauscher G, Felk S, Gillardon F, Tumani H (Apr 2007). "Proteome analysis of cerebrospinal fluid in Guillain–Barré syndrome (GBS)". Journal of Neuroimmunology. 185 (1–2): 190–4. doi:10.1016/j.jneuroim.2007.01.022. PMID17367871.
↑Ziemnicka-Kotula D, Xu J, Gu H, Potempska A, Kim KS, Jenkins EC, Trenkner E, Kotula L (May 1998). "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. doi:10.1074/jbc.273.22.13681. PMID9593709.
↑ 25.025.1McMahon LW, Sangerman J, Goodman SR, Kumaresan K, Lambert MW (June 2001). "Human alpha spectrin II and the FANCA, FANCC, and FANCG proteins bind to DNA containing psoralen interstrand cross-links". Biochemistry. 40 (24): 7025–34. doi:10.1021/bi002917g. PMID11401546.
↑ 26.026.1McMahon LW, Walsh CE, Lambert MW (November 1999). "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. doi:10.1074/jbc.274.46.32904. PMID10551855.
↑Sridharan D, Brown M, Lambert WC, McMahon LW, Lambert MW (March 2003). "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. doi:10.1242/jcs.00294. PMID12571280.
↑Hirai H, Matsuda S (September 1999). "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. doi:10.1016/s0168-0102(99)00061-9. PMID10576550.
↑ 29.029.1Brown MJ, Hallam JA, Liu Y, Yamada KM, Shaw S (July 2001). "Cutting edge: integration of human T lymphocyte cytoskeleton by the cytolinker plectin". J. Immunol. 167 (2): 641–5. doi:10.4049/jimmunol.167.2.641. PMID11441066.
↑Herrmann H, Wiche G (January 1987). "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. PMID3027087.
↑Böckers TM, Mameza MG, Kreutz MR, Bockmann J, Weise C, Buck F, Richter D, Gundelfinger ED, Kreienkamp HJ (October 2001). "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. doi:10.1074/jbc.M102454200. PMID11509555.
Further reading
Chow CW (1999). "Regulation and intracellular localization of the epithelial isoforms of the Na+/H+ exchangers NHE2 and NHE3". Clinical and investigative medicine. Médecine clinique et experimentale. 22 (5): 195–206. PMID10579058.
Hayashi Y, Arakaki R, Ishimaru N (2003). "The role of caspase cascade on the development of primary Sjögren's syndrome". J. Med. Invest. 50 (1–2): 32–8. PMID12630566.
Bennett V (1979). "Immunoreactive forms of human erythrocyte ankyrin are present in diverse cells and tissues". Nature. 281 (5732): 597–9. doi:10.1038/281597a0. PMID492324.
Davis LH, Bennett V (1990). "Mapping the binding sites of human erythrocyte ankyrin for the anion exchanger and spectrin". J. Biol. Chem. 265 (18): 10589–96. PMID2141335.
Moon RT, McMahon AP (1990). "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. PMID2307671.
Langley RC, Cohen CM (1986). "Association of spectrin with desmin intermediate filaments". J. Cell. Biochem. 30 (2): 101–9. doi:10.1002/jcb.240300202. PMID2939097.
Cianci CD, Giorgi M, Morrow JS (1988). "Phosphorylation of ankyrin down-regulates its cooperative interaction with spectrin and protein 3". J. Cell. Biochem. 37 (3): 301–15. doi:10.1002/jcb.240370305. PMID2970468.
Steiner JP, Bennett V (1988). "Ankyrin-independent membrane protein-binding sites for brain and erythrocyte spectrin". J. Biol. Chem. 263 (28): 14417–25. PMID2971657.
Herrmann H, Wiche G (1987). "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. PMID3027087.
McMahon AP, Giebelhaus DH, Champion JE, Bailes JA, Lacey S, Carritt B, Henchman SK, Moon RT (1987). "cDNA cloning, sequencing and chromosome mapping of a non-erythroid spectrin, human alpha-fodrin". Differentiation. 34 (1): 68–78. doi:10.1111/j.1432-0436.1987.tb00052.x. PMID3038643.
Frappier T, Regnouf F, Pradel LA (1988). "Binding of brain spectrin to the 70-kDa neurofilament subunit protein". Eur. J. Biochem. 169 (3): 651–7. doi:10.1111/j.1432-1033.1987.tb13657.x. PMID3121319.
McMahon AP, Moon RT (1988). "Structure and evolution of a non-erythroid spectrin, human alpha-fodrin". Biochem. Soc. Trans. 15 (5): 804–7. PMID3691949.
Lundberg S, Björk J, Löfvenberg L, Backman L (1995). "Cloning, expression and characterization of two putative calcium-binding sites in human non-erythroid alpha-spectrin". Eur. J. Biochem. 230 (2): 658–65. doi:10.1111/j.1432-1033.1995.0658h.x. PMID7607240.
Hughes CA, Bennett V (1995). "Adducin: a physical model with implications for function in assembly of spectrin-actin complexes". J. Biol. Chem. 270 (32): 18990–6. doi:10.1074/jbc.270.32.18990. PMID7642559.
Li X, Bennett V (1996). "Identification of the spectrin subunit and domains required for formation of spectrin/adducin/actin complexes". J. Biol. Chem. 271 (26): 15695–702. doi:10.1074/jbc.271.26.15695. PMID8663089.
Stabach PR, Cianci CD, Glantz SB, Zhang Z, Morrow JS (1997). "Site-directed mutagenesis of alpha II spectrin at codon 1175 modulates its mu-calpain susceptibility". Biochemistry. 36 (1): 57–65. doi:10.1021/bi962034i. PMID8993318.
1m8m: SOLID-STATE MAS NMR STRUCTURE OF THE A-SPECTRIN SH3 DOMAIN
PDB 1pwt EBI.jpg
1pwt: THERMODYNAMIC ANALYSIS OF ALPHA-SPECTRIN SH3 AND TWO OF ITS CIRCULAR PERMUTANTS WITH DIFFERENT LOOP LENGTHS: DISCERNING THE REASONS FOR RAPID FOLDING IN PROTEINS
PDB 1qkw EBI.jpg
1qkw: ALPHA-SPECTRIN SRC HOMOLOGY 3 DOMAIN, N47G MUTANT IN THE DISTAL LOOP.
PDB 1qkx EBI.jpg
1qkx: ALPHA-SPECTRIN SRC HOMOLOGY 3 DOMAIN, N47A MUTANT IN THE DISTAL LOOP.
PDB 1shg EBI.jpg
1shg: CRYSTAL STRUCTURE OF A SRC-HOMOLOGY 3 (SH3) DOMAIN
PDB 1u06 EBI.jpg
1u06: crystal structure of chicken alpha-spectrin SH3 domain
PDB 1u4q EBI.jpg
1u4q: Crystal Structure of Repeats 15, 16 and 17 of Chicken Brain Alpha Spectrin
PDB 1u5p EBI.jpg
1u5p: Crystal Structure of Repeats 15 and 16 of Chicken Brain Alpha Spectrin
PDB 1uue EBI.jpg
1uue: A-SPECTRIN SH3 DOMAIN (V44T, D48G MUTANT)
PDB 2cdt EBI.jpg
2cdt: ALPHA-SPECTRIN SH3 DOMAIN A56S MUTANT
PDB 2f2v EBI.jpg
2f2v: alpha-spectrin SH3 domain A56G mutant
PDB 2f2w EBI.png
2f2w: alpha-spectrin SH3 domain R21A mutant
PDB 2f2x EBI.png
2f2x: alpha-spectrin SH3 domain R21G mutant
PDB 2fot EBI.png
2fot: Crystal structure of the complex between calmodulin and alphaII-spectrin
PDB 2jm8 EBI.png
2jm8: R21A Spc-SH3 free
PDB 2jm9 EBI.png
2jm9: R21A Spc-SH3 bound
PDB 2jma EBI.png
2jma: R21A Spc-SH3:P41 complex
PDB 2nuz EBI.jpg
2nuz: crystal structure of alpha spectrin SH3 domain measured at room temperature