| Structural highlights
Disease
[SPTA1_HUMAN] Defects in SPTA1 are the cause of elliptocytosis type 2 (EL2) [MIM:130600]. EL2 is a Rhesus-unlinked form of hereditary elliptocytosis, a genetically heterogeneous, autosomal dominant hematologic disorder. It is characterized by variable hemolytic anemia and elliptical or oval red cell shape.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] Defects in SPTA1 are a cause of hereditary pyropoikilocytosis (HPP) [MIM:266140]. HPP is an autosomal recessive disorder characterized by hemolytic anemia, microspherocytosis, poikilocytosis, and an unusual thermal sensitivity of red cells.[13] Defects in SPTA1 are the cause of spherocytosis type 3 (SPH3) [MIM:270970]; also known as hereditary spherocytosis type 3 (HS3). Spherocytosis is a hematologic disorder leading to chronic hemolytic anemia and characterized by numerous abnormally shaped erythrocytes which are generally spheroidal. SPH3 is characterized by severe hemolytic anemia. Inheritance is autosomal recessive.
Function
[SPTA1_HUMAN] Spectrin is the major constituent of the cytoskeletal network underlying the erythrocyte plasma membrane. It associates with band 4.1 and actin to form the cytoskeletal superstructure of the erythrocyte plasma membrane.
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
We have determined the solution NMR structure of a recombinant peptide that consists of the first 156 residues of erythroid alpha-spectrin. The first 20 residues preceding the first helix (helix C') are in a disordered conformation. The subsequent three helices (helices A1, B1, and C1) form a triple helical bundle structural domain that is similar, but not identical, to previously published structures for spectrin from Drosophila and chicken brain. Paramagnetic spin label-induced NMR resonance broadening shows that helix C', the partial domain involved in alpha- and beta-spectrin association, exhibits little interaction with the structural domain. Surprisingly, helix C' is connected to helix A1 of the structural domain by a segment of 7 residues (the junction region) that exhibits a flexible disordered conformation, in contrast to the predicted rigid helical structure. We suggest that the flexibility of this particular junction region may play an important role in modulating the association affinity of alpha- and beta-spectrin at the tetramerization site of different isoforms, such as erythroid spectrin and brain spectrin. These findings may provide insight for explaining various physiological and pathological conditions that are a consequence of varying alpha- and beta-subunit self-association affinities in their formation of the various spectrin tetramers.
Solution structural studies on human erythrocyte alpha-spectrin tetramerization site.,Park S, Caffrey MS, Johnson ME, Fung LW J Biol Chem. 2003 Jun 13;278(24):21837-44. Epub 2003 Apr 1. PMID:12672815[14]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Sahr KE, Tobe T, Scarpa A, Laughinghouse K, Marchesi SL, Agre P, Linnenbach AJ, Marchesi VT, Forget BG. Sequence and exon-intron organization of the DNA encoding the alpha I domain of human spectrin. Application to the study of mutations causing hereditary elliptocytosis. J Clin Invest. 1989 Oct;84(4):1243-52. PMID:2794061 doi:http://dx.doi.org/10.1172/JCI114291
- ↑ Parquet N, Devaux I, Boulanger L, Galand C, Boivin P, Lecomte MC, Dhermy D, Garbarz M. Identification of three novel spectrin alpha I/74 mutations in hereditary elliptocytosis: further support for a triple-stranded folding unit model of the spectrin heterodimer contact site. Blood. 1994 Jul 1;84(1):303-8. PMID:8018926
- ↑ Coetzer TL, Sahr K, Prchal J, Blacklock H, Peterson L, Koler R, Doyle J, Manaster J, Palek J. Four different mutations in codon 28 of alpha spectrin are associated with structurally and functionally abnormal spectrin alpha I/74 in hereditary elliptocytosis. J Clin Invest. 1991 Sep;88(3):743-9. PMID:1679439 doi:http://dx.doi.org/10.1172/JCI115371
- ↑ Floyd PB, Gallagher PG, Valentino LA, Davis M, Marchesi SL, Forget BG. Heterogeneity of the molecular basis of hereditary pyropoikilocytosis and hereditary elliptocytosis associated with increased levels of the spectrin alpha I/74-kilodalton tryptic peptide. Blood. 1991 Sep 1;78(5):1364-72. PMID:1878597
- ↑ Lecomte MC, Garbarz M, Grandchamp B, Feo C, Gautero H, Devaux I, Bournier O, Galand C, d'Auriol L, Galibert F, et al.. Sp alpha I/78: a mutation of the alpha I spectrin domain in a white kindred with HE and HPP phenotypes. Blood. 1989 Aug 15;74(3):1126-33. PMID:2568862
- ↑ Gallagher PG, Tse WT, Coetzer T, Lecomte MC, Garbarz M, Zarkowsky HS, Baruchel A, Ballas SK, Dhermy D, Palek J, et al.. A common type of the spectrin alpha I 46-50a-kD peptide abnormality in hereditary elliptocytosis and pyropoikilocytosis is associated with a mutation distant from the proteolytic cleavage site. Evidence for the functional importance of the triple helical model of spectrin. J Clin Invest. 1992 Mar;89(3):892-8. PMID:1541680 doi:http://dx.doi.org/10.1172/JCI115669
- ↑ Dalla Venezia N, Alloisio N, Forissier A, Denoroy L, Aymerich M, Vives-Corrons JL, Besalduch J, Besson I, Delaunay J. Elliptopoikilocytosis associated with the alpha 469 His-->Pro mutation in spectrin Barcelona (alpha I/50-46b). Blood. 1993 Sep 1;82(5):1661-5. PMID:8364215
- ↑ Morle L, Roux AF, Alloisio N, Pothier B, Starck J, Denoroy L, Morle F, Rudigoz RC, Forget BG, Delaunay J, et al.. Two elliptocytogenic alpha I/74 variants of the spectrin alpha I domain. Spectrin Culoz (GGT----GTT; alpha I 40 Gly----Val) and spectrin Lyon (CTT----TTT; alpha I 43 Leu---Phe). J Clin Invest. 1990 Aug;86(2):548-54. PMID:2384601 doi:http://dx.doi.org/10.1172/JCI114743
- ↑ Alloisio N, Wilmotte R, Morle L, Baklouti F, Marechal J, Ducluzeau MT, Denoroy L, Feo C, Forget BG, Kastally R, et al.. Spectrin Jendouba: an alpha II/31 spectrin variant that is associated with elliptocytosis and carries a mutation distant from the dimer self-association site. Blood. 1992 Aug 1;80(3):809-15. PMID:1638030
- ↑ Morle L, Morle F, Roux AF, Godet J, Forget BG, Denoroy L, Garbarz M, Dhermy D, Kastally R, Delaunay J. Spectrin Tunis (Sp alpha I/78), an elliptocytogenic variant, is due to the CGG----TGG codon change (Arg----Trp) at position 35 of the alpha I domain. Blood. 1989 Aug 1;74(2):828-32. PMID:2568861
- ↑ Perrotta S, Miraglia del Giudice E, Alloisio N, Sciarratta G, Pinto L, Delaunay J, Cutillo S, Iolascon A. Mild elliptocytosis associated with the alpha 34 Arg-->Trp mutation in spectrin Genova (alpha I/74). Blood. 1994 Jun 1;83(11):3346-9. PMID:8193371
- ↑ Perrotta S, Iolascon A, De Angelis F, Pagano L, Colonna G, Cutillo S, Miraglia del Giudice E. Spectrin Anastasia (alpha I/78): a new spectrin variant (alpha 45 Arg-->Thr) with moderate elliptocytogenic potential. Br J Haematol. 1995 Apr;89(4):933-6. PMID:7772539
- ↑ Floyd PB, Gallagher PG, Valentino LA, Davis M, Marchesi SL, Forget BG. Heterogeneity of the molecular basis of hereditary pyropoikilocytosis and hereditary elliptocytosis associated with increased levels of the spectrin alpha I/74-kilodalton tryptic peptide. Blood. 1991 Sep 1;78(5):1364-72. PMID:1878597
- ↑ Park S, Caffrey MS, Johnson ME, Fung LW. Solution structural studies on human erythrocyte alpha-spectrin tetramerization site. J Biol Chem. 2003 Jun 13;278(24):21837-44. Epub 2003 Apr 1. PMID:12672815 doi:10.1074/jbc.M300617200
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