Advertisement

Science China Life Sciences

, Volume 56, Issue 12, pp 1076–1085 | Cite as

Spectrin: Structure, function and disease

  • Rui Zhang
  • ChenYu Zhang
  • Qi Zhao
  • DongHai LiEmail author
Open Access
Review

Abstract

Spectrin is a large, cytoskeletal, and heterodimeric protein composed of modular structure of α and β subunits, it typically contains 106 contiguous amino acid sequence motifs called “spectrin repeats”. Spectrin is crucial for maintaining the stability and structure of the cell membrane and the shape of a cell. Moreover, it contributes to diverse cell functions such as cell adhesion, cell spreading, and the cell cycle. Mutations of spectrin lead to various human diseases such as hereditary hemolytic anemia, type 5 spinocerebellar ataxia, cancer, as well as others. This review focuses on recent advances in determining the structure and function of spectrin as well as its role in disease.

Keywords

erythrocyte spectrin cell cycle mass spectrometry disease 

References

  1. 1.
    Marchesi V, Steers Jr E. Selective solubilization of a protein component of the red cell membrane. Science, 1968, 159: 203–204PubMedCrossRefGoogle Scholar
  2. 2.
    Hartwig J H. Actin-binding proteins 1: Spectrin superfamily. Protein Profile, 1995, 2: 703–800PubMedGoogle Scholar
  3. 3.
    Naydenov N G, Ivanov A I. Spectrin-adducin membrane skeleton: A missing link between epithelial junctions and the actin cytoskeletion? Bioarchitecture, 2011, 1: 186–191PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Elgsaeter A, Stokke B T, Mikkelsen A, et al. The molecular basis of erythrocyte shape. Science, 1986, 234: 1217–1723PubMedCrossRefGoogle Scholar
  5. 5.
    Stankewich M C, Cianci C D, Stabach P R, et al. Cell organization, growth, and neural and cardiac development require alphaII-spectrin. J Cell Sci, 2011, 124: 3956–3966PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Cianci C D, Zhang Z, Pradhan D, et al. Brain and muscle express a unique alternative transcript of αII spectrin. Biochemistry, 1999, 38: 15721–15730PubMedCrossRefGoogle Scholar
  7. 7.
    Moon R T, McMahon A P. Generation of diversity in nonerythroid spectrins. Multiple polypeptides are predicted by sequence analysis of cDNAs encompassing the coding region of human nonerythroid α-spectrin. J Biol Chem, 1990, 265: 4427–4433PubMedGoogle Scholar
  8. 8.
    Machnicka B, Grochowalska R, Boguslawska D M, et al. Spectrin-based skeleton as an actor in cell signaling. Cell Mol Life Sci, 2012, 69: 191–201PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Dubreuil R R, Grushko T. Genetic studies of spectrin: New life for a ghost protein. Bioessays, 1998, 20: 875–878PubMedCrossRefGoogle Scholar
  10. 10.
    Viel A. α-Actinin and spectrin structures: An unfolding family story. FEBS Lett, 1999, 460: 391–394PubMedCrossRefGoogle Scholar
  11. 11.
    Grum V L, Li D, MacDonald R I, et al. Structures of two repeats of spectrin suggest models of flexibility. Cell, 1999, 98: 523–535PubMedCrossRefGoogle Scholar
  12. 12.
    Ipsaro J J, Harper S L, Messick T E, et al. Crystal structure and functional interpretation of the erythrocyte spectrin tetramerization domain complex. Blood, 2010, 115: 4843–4852PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Brenner A K, Kieffer B, Travé G, et al. Thermal stability of chicken brain α-spectrin repeat 17: A spectroscopic study. J Biomol NMR, 2012, 53: 71–83PubMedCrossRefGoogle Scholar
  14. 14.
    Kusunoki H, Minasov G, MacDonald R I, et al. Independent movement, dimerization and stability of tandem repeats of chicken brain α-spectrin. J Mol Biol, 2004, 344: 495–511PubMedCrossRefGoogle Scholar
  15. 15.
    Li D, Harper S L, Tang H Y, et al. A comprehensive model of the spectrin divalent tetramer binding region deduced using homology modeling and chemical cross-linking of a mini-spectrin. J Biol Chem, 2010, 285: 29535–29545PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Harper S L, Li D, Maksimova Y, et al. A fused α-β “mini-spectrin” mimics the intact erythrocyte spectrin head-to-head tetramer. J Biol Chem, 2010, 285: 11003–11012PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Li D, Tang H Y, Speicher D W. A structural model of the erythrocyte spectrin heterodimer initiation site determined using homology modeling and chemical cross-linking. J Biol Chem, 2008, 283: 1553–1562PubMedCrossRefGoogle Scholar
  18. 18.
    Li D, Harper S, David W. Initiation and propagation of spectrin heterodimer assembly involves distinct energetic processes. Biochemistry, 2007, 46: 10585–10594PubMedCrossRefGoogle Scholar
  19. 19.
    Koshino I, Mohandas N, Takakuwa Y. Identification of a novel role for dematin in regulating red cell membrane function by modulating spectrin-actin interaction. J Biol Chem, 2012, 287: 35244–35250PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Zhang P, Talluri S, Deng H, et al. Solution structure of the pleckstrin homology domain of Drosophila β spectrin. Structure, 1995, 3: 1185–1195PubMedCrossRefGoogle Scholar
  21. 21.
    Bennett V, Healy J. Organizing the fluid membrane bilayer: diseases linked to spectrin and ankyrin. Trends Mol Med, 2008, 14: 28–36PubMedCrossRefGoogle Scholar
  22. 22.
    Wu S, Sangerman J, Li M, et al. Essential control of an endothelial cell ISOC by the spectrin membrane skeleton. J Cell Biol, 2001, 154: 1225–1234PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Kizhatil K, Yoon W, Mohler P J, et al. Ankyrin-G and β2-spectrin collaborate in biogenesis of lateral membrane of human bronchial epithelial cells. J Biol Chem, 2007, 282: 2029–2037PubMedCrossRefGoogle Scholar
  24. 24.
    Devarajan P, Stabach P R, De Matteis M A, et al. Na, K-ATPase transport from endoplasmic reticulum to Golgi requires the Golgi spectrin-ankyrin G119 skeleton in Madin Darby canine kidney cells. Proc Natl Acad Sci USA, 1997, 94: 10711–10716PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Cairo C W, Das R, Albohy A, et al. Dynamic regulation of CD45 lateral mobility by the spectrin-ankyrin cytoskeleton of T cells. J Biol Chem, 2010, 285: 11392–11401PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Zhang D Q, Wang Y P, Wang W H, et al. Interaction between protein 4.1R and spectrin heterodimers. Mol Med Report, 2011, 4: 651–654Google Scholar
  27. 27.
    Gimm J A, An X, Nunomura W, et al. Functional characterization of spectrin-actin-binding domains in 4.1 family of proteins. Biochemistry, 2002, 41: 7275–7282PubMedCrossRefGoogle Scholar
  28. 28.
    An X, Debnath G, Guo X, et al. Identification and functional characterization of protein 4.1 R and actin-binding sites in erythrocyte β spectrin: Regulation of the interactions by phosphatidylinositol-4, 5-bisphosphate. Biochemistry, 2005, 44: 10681–10688PubMedCrossRefGoogle Scholar
  29. 29.
    Becker P, Tse W, Lux S, et al. Beta spectrin kissimmee: A spectrin variant associated with autosomal dominant hereditary spherocytosis and defective binding to protein 4.1. J Clin Invest, 1993, 92: 612–616PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Tse W T, Lux S E. Red blood cell membrane disorders. Br J Haematol, 1999, 104: 2–13PubMedCrossRefGoogle Scholar
  31. 31.
    Urwyler O, Cortinas-Elizondo F, Suter B. Drosophila sosie functions with beta(H)-spectrin and actin organizers in cell migration, epithelial morphogenesis and cortical stability. Biol Open, 2012, 1: 994–1005PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Gushchina L V, Gabdulkhakov A G, Nikonov S V, et al. High-resolution crystal structure of spectrin SH3 domain fused with a proline-rich peptide. J Biomol Struct Dyn, 2011, 29: 485–495PubMedCrossRefGoogle Scholar
  33. 33.
    Bialkowska K, Saido T C, Fox J E. SH3 domain of spectrin participates in the activation of Rac in specialized calpain-induced integrin signaling complexes. J Cell Sci, 2005, 118: 381–395PubMedCrossRefGoogle Scholar
  34. 34.
    Collec E, Lecomte M C, El Nemer W, et al. Novel role for the Lu/BCAM-spectrin interaction in actin cytoskeleton reorganization. Biochem J, 2011, 436: 699–708PubMedCrossRefGoogle Scholar
  35. 35.
    Benz P M, Blume C, Moebius J, et al. Cytoskeleton assembly at endothelial cell-cell contacts is regulated by alpha II-spectrin-VASP complexes. J Cell Biol, 2008, 180: 205–219PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Rotter B, Bournier O, Nicolas G, et al. αII-Spectrin interacts with Tes and EVL, two actin-binding proteins located at cell contacts. Biochem J, 2005, 388: 631–638PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Benz P M, Merkel C J, Offner K, et al. Mena/VASP and alphaII-spectrin complexes regulate cytoplasmic actin networks in cardiomyocytes and protect from conduction abnormalities and dilated cardiomyopathy. Cell Commun Signal, 2013, 11: 56PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Mishra L, Cai T, Levine A, et al. Identification of elf1, a beta-spectrin, in early mouse liver development. Int J Dev Biol, 1998, 42: 221–224PubMedGoogle Scholar
  39. 39.
    Mishra L, Cai T, Yu P, et al. Elf3 encodes a novel 200-kD beta-spectrin: Role in liver development. Oncogene, 1999, 18: 353–364PubMedCrossRefGoogle Scholar
  40. 40.
    Tang Y, Katuri V, Dillner A, et al. Disruption of transforming growth factor-beta signaling in ELF beta-spectrin-deficient mice. Science, 2003, 299: 574–577PubMedCrossRefGoogle Scholar
  41. 41.
    Mishra B, Tang Y, Katuri V, et al. Loss of cooperative function of transforming growth factor-beta signaling proteins, smad3 with embryonic liver fodrin, a beta-spectrin, in primary biliary cirrhosis. Liver Int, 2004, 24: 637–645PubMedCrossRefGoogle Scholar
  42. 42.
    Redman R S, Katuri V, Tang Y, et al. Orofacial and gastrointestinal hyperplasia and neoplasia in smad4+/− and elf+/−/smad4+/− mutant mice. J Oral Pathol Med, 2005, 34: 23–29PubMedCrossRefGoogle Scholar
  43. 43.
    Stabach P R, Morrow J S. Identification and characterization of βV spectrin, a mammalian ortholog of Drosophila βHspectrin. J Biol Chem, 2000, 275: 21385–21395PubMedCrossRefGoogle Scholar
  44. 44.
    Godi A, Santone I, Pertile P, et al. ADP ribosylation factor regulates spectrin binding to the Golgi complex. Proc Natl Acad Sci USA, 1998, 95: 8607–8612PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    de Matteis M A, Morrow J S. Spectrin tethers and mesh in the biosynthetic pathway. J Cell Sci, 2000, 113: 2331–2343PubMedGoogle Scholar
  46. 46.
    Salcedo-Sicilia L, Granell S, Jovic M, et al. betaIII spectrin regulates the structural integrity and the secretory protein transport of the Golgi complex. J Biol Chem, 2013, 288: 2157–2166PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Sridharan D, Brown M, Lambert W C, et al. Nonerythroid alphaII spectrin is required for recruitment of FANCA and XPF to nuclear foci induced by DNA interstrand cross-links. J Cell Sci, 2003, 116: 823–835PubMedCrossRefGoogle Scholar
  48. 48.
    McMahon L W, Zhang P, Sridharan D M, et al. Knockdown of alphaII spectrin in normal human cells by siRNA leads to chromosomal instability and decreased DNA interstrand cross-link repair. Biochem Biophys Res Commun, 2009, 381: 288–293PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Zhang P, Herbig U, Coffman F, et al. Non-erythroid alpha spectrin prevents telomere dysfunction after DNA interstrand cross-link damage. Nucleic Acids Res, 2013, 41: 5321–5340PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Machnicka B, Grochowalska R, Bogusławska D, et al. Spectrin-based skeleton as an actor in cell signaling. Cell Mol Life Sci, 2012, 69: 191–201PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Grzybek M, Chorzalska A, Bok E, et al. Spectrin-phospholipid interactions: Existence of multiple kinds of binding sites? Chem Phys Lipids, 2006, 141: 133–141PubMedCrossRefGoogle Scholar
  52. 52.
    Manno S, Takakuwa Y, Mohandas N. Identification of a functional role for lipid asymmetry in biological membranes: Phosphatidylserine-skeletal protein interactions modulate membrane stability. Proc Natl Acad Sci USA, 2002, 99: 1943–1948PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Ray S, Chakrabarti A. Membrane interaction of erythroid spectrin: Surface-density-dependent high-affinity binding to phosphatidylethanolamine. Mol Membr Biol, 2004, 21: 93–100PubMedCrossRefGoogle Scholar
  54. 54.
    Wolny M, Grzybek M, Bok E, et al. Key amino acid residues of ankyrin-sensitive phosphatidylethanolamine/phosphatidylcholine-lipid binding site of βI-spectrin. PLoS ONE, 2011, 6: e21538PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Czogalla A, Grzymajło K, Jezierski A, et al. Phospholipid-induced structural changes to an erythroid β spectrin ankyrin-dependent lipid-binding site. Biochim Biophys Acta, 2008, 1778: 2612–2620PubMedCrossRefGoogle Scholar
  56. 56.
    Lecomte M C. Spectrins in human diseases. Cytoskeleton Hum Dis, 2012, 345–374CrossRefGoogle Scholar
  57. 57.
    Harper S L, Sriswasdi S, Tang H Y, et al. The common hereditary elliptocytosis-associated alpha-spectrin L260P mutation perturbs erythrocyte membranes by stabilizing spectrin in the closed dimer conformation. Blood, 2013, 122: 3045–3053PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Miraglia del Giudice E, Nobili B, Francese M, et al. Clinical and molecular evaluation of non-dominant hereditary spherocytosis. Br J Haematol, 2001, 112: 42–47PubMedCrossRefGoogle Scholar
  59. 59.
    Sakaguchi G, Orita S, Naito A, et al. A novel brain-specific isoform of beta spectrin: Isolation and its interaction with Munc13. Biochem Biophys Res Commun, 1998, 248: 846–851PubMedCrossRefGoogle Scholar
  60. 60.
    Featherstone D E, Davis W S, Dubreuil R R, et al. Drosophila α-and β-spectrin mutations disrupt presynaptic neurotransmitter release. J Neurosci, 2001, 21: 4215–4224PubMedGoogle Scholar
  61. 61.
    Ayala-Grosso C, Tam J, Roy S, et al. Caspase-3 cleaved spectrin colocalizes with neurofilament-immunoreactive neurons in Alzheimer’s disease. Neuroscience, 2006, 141: 863–874PubMedCrossRefGoogle Scholar
  62. 62.
    Jackson M, Song W, Liu M Y, et al. Modulation of the neuronal glutamate transporter EAAT4 by two interacting proteins. Nature, 2001, 410: 89–93PubMedCrossRefGoogle Scholar
  63. 63.
    Waller K L, Nunomura W, An X, et al. Mature parasite-infected erythrocyte surface antigen (MESA) of Plasmodium falciparum binds to the 30-kDa domain of protein 4.1 in malaria-infected red blood cells. Blood, 2003, 102: 1911–1914PubMedCrossRefGoogle Scholar
  64. 64.
    Magowan C, Coppel R, Lau A, et al. Role of the Plasmodium falciparum mature-parasite-infected erythrocyte surface antigen (MESA/PfEMP-2) in malarial infection of erythrocytes. Blood, 1995, 86: 3196–3204PubMedGoogle Scholar
  65. 65.
    Pei X, An X, Guo X, et al. Structural and functional studies of interaction between Plasmodium falciparum knob-associated histidine-rich protein (KAHRP) and erythrocyte spectrin. J Biol Chem, 2005, 280: 31166–31171PubMedCrossRefGoogle Scholar
  66. 66.
    Herrera S, Rudin W, Herrera M, et al. A conserved region of the MSP-1 surface protein of Plasmodium falciparum contains a recognition sequence for erythrocyte spectrin. EMBO J, 1993, 12: 1607–1614PubMedPubMedCentralGoogle Scholar
  67. 67.
    Ruetz T J, Lin A E, Guttman J A. Enterohaemorrhagic Escherichia coli requires the spectrin cytoskeleton for efficient attachment and pedestal formation on host cells. Microb Pathog, 2012, 52: 149–156PubMedCrossRefGoogle Scholar
  68. 68.
    Samanta S, Dutta D, Ghoshal A, et al. Glycosylation of erythrocyte spectrin and its modification in visceral leishmaniasis. PLoS ONE, 2011, 6: e28169PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Samanta S, Ghoshal A, Bhattacharya K, et al. Sialoglycosylation of RBC in visceral leishmaniasis leads to enhanced oxidative stress, calpain-induced fragmentation of spectrin and hemolysis. PLoS ONE, 2012, 7: e42361PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Papal S, Cortese M, Legendre K, et al. The giant spectrin betaV couples the molecular motors to phototransduction and Usher syndrome type I proteins along their trafficking route. Hum Mol Genet, 2013, 22: 3773–3788PubMedCrossRefGoogle Scholar
  71. 71.
    Witek M A, Fung L W. Quantitative studies of caspase-3 catalyzed alphaII-spectrin breakdown. Brain Res, 2013, doi: 10.1016/j.brainres.2013.08.010Google Scholar
  72. 72.
    Toporkiewicz M, Grzybek M, Meissner J, et al. Release of an ∼55 kDa fragment containing the actin-binding domain of beta-spectrin by caspase-8 during FND-induced apoptosis depends on the presence of protein 4.1. Arch Biochem Biophys, 2013, 535: 205–213PubMedCrossRefGoogle Scholar
  73. 73.
    Yang H, Zhang H, Zhu L, et al. Pathway analysis of cancer-associated microRNA targets. Int J Oncol, 2012, 41: 2213–2226PubMedGoogle Scholar
  74. 74.
    Zhang H, Yang H, Zhang R, et al. In-depth bioinformatic analysis of lung cancer-associated microRNA targets. Oncol Rep, 2013, 30: 2945–2956PubMedGoogle Scholar

Copyright information

© The Author(s) 2013

Authors and Affiliations

  1. 1.Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life SciencesNanjing UniversityNanjingChina
  2. 2.Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced TechnologyChinese Academy of SciencesShenzhenChina

Personalised recommendations