SPTAN1

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. As opposed to alpha I-spectrin that is principally found in erythrocytes, 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, and in cardiac fibroblasts along the surface of the cytoskeletal network. Alpha II-spectrin most commonly exists in a heterodimer with alpha II and beta II spectrin subunits; and dimers typically self-associate and heterotetramerize.

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. 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. 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. 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. 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. Fourthly, a six amino acid insert in the twenty-first spectrin motif with unknown function has been reported.

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

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.

Clinical significance

Mutations in SPTAN1 are the cause of early infantile epileptic encephalopathy-5.

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. Elevated protein expression of alpha II-spectrin has been detected in cerebrospinal fluid in patients with Guillain–Barré syndrome.

Interactions

SPTAN1 has been shown to interact with:

• Abl gene,
• FANCA,
• Fanconi anemia, complementation group C,
• GRIA2,
• Plectin,
• SHANK1, and
• Vimentin.

References

References

1. (February 1988). "Comparison of nonerythroid alpha-spectrin genes reveals strict homology among diverse species". Molecular and Cellular Biology.
2. (Jan 1988). "Entrez Gene: SPTAN1 spectrin, alpha, non-erythrocytic 1 (alpha-fodrin)". Molecular and Cellular Biology.
3. (1987). "cDNA cloning, sequencing and chromosome mapping of a non-erythroid spectrin, human alpha-fodrin". Differentiation; Research in Biological Diversity.
4. (Jun 2010). "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.
5. (Nov 1999). "Brain and muscle express a unique alternative transcript of alphaII spectrin". Biochemistry.
6. (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.
7. (Jun 2008). "Cardiac myofibrillogenesis inside intact embryonic hearts". Developmental Biology.
8. (Apr 2006). "The transitional junction: a new functional subcellular domain at the intercalated disc". Molecular Biology of the Cell.
9. (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.
10. (Sep 1993). "Alpha-spectrin in detergent-extracted whole-mount cytoskeletons of chicken embryo heart fibroblasts". The Histochemical Journal.
11. (Sep 2003). "Spectrin alpha II and beta II isoforms interact with high affinity at the tetramerization site". The Biochemical Journal.
12. (1 September 2005). "The spectrin-associated cytoskeleton in mammalian heart". Frontiers in Bioscience: A Journal and Virtual Library.
13. (Mar 2007). "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.
14. (Jan 2009). "AlphaII-spectrin is critical for cell adhesion and cell cycle". The Journal of Biological Chemistry.
15. (Nov 2006). "alphaII-Spectrin interacts with five groups of functionally important proteins in the nucleus". Cell Biology International.
16. (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.
17. (Oct 1991). "Ankyrin binds to the 15th repetitive unit of erythroid and nonerythroid beta-spectrin". The Journal of Cell Biology.
18. (May 2000). "Caenorhabditis elegans beta-G spectrin is dispensable for establishment of epithelial polarity, but essential for muscular and neuronal function". The Journal of Cell Biology.
19. (2006). "Identification of differentially expressed genes induced by angiotensin II in rat cardiac fibroblasts". Clinical and Experimental Pharmacology & Physiology.
20. (Aug 2009). "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.
21. (Jun 2012). "Early onset West syndrome with severe hypomyelination and coloboma-like optic discs in a girl with SPTAN1 mutation". Epilepsia.
22. (Mar 2014). "Detection of alpha II-spectrin breakdown products in the serum of neonates with congenital heart disease*". Pediatric Critical Care Medicine.
23. (Apr 2007). "Proteome analysis of cerebrospinal fluid in Guillain–Barré syndrome (GBS)". Journal of Neuroimmunology.
24. (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". Journal of Biological Chemistry.
25. (March 2003). "Nonerythroid alphaII spectrin is required for recruitment of FANCA and XPF to nuclear foci induced by DNA interstrand cross-links". Journal of Cell Science.
26. (June 2001). "Human alpha spectrin II and the FANCA, FANCC, and FANCG proteins bind to DNA containing psoralen interstrand cross-links". Biochemistry.
27. (November 1999). "Human alpha spectrin II and the Fanconi anemia proteins FANCA and FANCC interact to form a nuclear complex". Journal of Biological Chemistry.
28. (September 1999). "Interaction of the C-terminal domain of delta glutamate receptor with spectrin in the dendritic spines of cultured Purkinje cells". Neuroscience Research.
29. (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". Journal of Biological Chemistry.
30. (October 2001). "Synaptic scaffolding proteins in rat brain. Ankyrin repeats of the multidomain Shank protein family interact with the cytoskeletal protein alpha-fodrin". Journal of Biological Chemistry.
31. (July 2001). "Cutting edge: integration of human T lymphocyte cytoskeleton by the cytolinker plectin". Journal of Immunology.