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Titolo:
EXON 46-ENCODED SEQUENCE IS ESSENTIAL FOR STABILITY OF HUMAN ERYTHROID ALPHA-SPECTRIN AND HETERODIMER FORMATION
Autore:
WILMOTTE R; HARPER SL; URSITTI JA; MARECHAL J; DELAUNAY J; SPEICHER DW;
Indirizzi:
WISTAR INST ANAT & BIOL,3601 SPRUCE ST PHILADELPHIA PA 19104 WISTAR INST ANAT & BIOL PHILADELPHIA PA 19104 INST PASTEUR,CNRS URA 1171,LAB GENET MOL HUMAINE LYON FRANCE
Titolo Testata:
Blood
fascicolo: 10, volume: 90, anno: 1997,
pagine: 4188 - 4196
SICI:
0006-4971(1997)90:10<4188:E4SIEF>2.0.ZU;2-0
Fonte:
ISI
Lingua:
ENG
Soggetto:
RED-CELL SPECTRIN; BETA-SPECTRIN; HEREDITARY ELLIPTOCYTOSIS; INTRON ORGANIZATION; FUNCTIONAL DOMAINS; BINDING; GENE; SITE; IDENTIFICATION; SEGMENTS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
30
Recensione:
Indirizzi per estratti:
Citazione:
R. Wilmotte et al., "EXON 46-ENCODED SEQUENCE IS ESSENTIAL FOR STABILITY OF HUMAN ERYTHROID ALPHA-SPECTRIN AND HETERODIMER FORMATION", Blood, 90(10), 1997, pp. 4188-4196

Abstract

Human erythroid alpha-spectrin alleles responsible for hereditary elliptocytosis (alpha(HE) alleles) undergo increased incorporation into red blood cell membranes when the polymorphism alpha(LELY) (LELY: LOW Expression LYon) occurs in trans. The alpha(LELY) polymorphism is characterized by a mutation in exon 40 at codon 1857 (CTA --> GTA, Leu --> Val) and the partial (50%) skipping of exon 46, which encodes residues2177-2182 (Wilmotte et al, J Clin Invest 91:2091, 1993). Both of these peptide sequence alterations are located within the region of the alpha-chain involved in initiating heterodimer assembly, and either or both mutations could potentially contribute to decreased incorporation of alpha-chains from the alpha(LELY) allele in heterozygotes into red blood cell membranes. These possibilities were evaluated by testing the protease resistance and in vitro binding properties of normal and mutant recombinant 4-motif alpha subunit peptides containing the dimer initiation region. The two forms of alpha spectrin produced by alternative mRNA splicing of the alpha(LELY) allele were represented by alpha 18-21(1857), peptide with the codon 1857 mutation and retaining the exon 46 encoded sequence, and alpha 18-21(1857-Delta 46) a peptide carrying both the 1857 codon mutation and the exon 46 deletion. The properties of these two recombinant peptides were compared with alpha 18-21, a peptide with the normal sequence at codon 1857 and retaining the exon 46 encoded sequence. The codon 1857 mutation does not adversely affect dimer formation, but it is responsible for the increased trypsin cleavage between the alpha IV and alpha V domains that was the characteristic feature initially used to identify the alpha(LELY) (Sp alpha(V/41)) polymorphism (Alloisio et al, J Clin Invest 87:2169, 1991). Deletion of the six amino acids encoded by exon 46 perturbs folding of the alpha 21 motif, because this region of the alpha 18-21(1857-Delta 46) peptide is rapidly degraded and this recombinant peptide is unusually prone to self-aggregation. Exon 46 deletion reduces, but does not eliminate, dimerization. Comparison of mild trypsin proteolytic products from an alpha(LELY) homozygote and the two alpha(LELY) recombinant peptides strongly suggests that little, if any, of the 50% of the alpha chains from the alpha(LELY) allele that contain the exon 46 deletion are incorporated into the mature erythroid membrane. Based on the in vitroanalysis of recombinant alpha(LELY) peptides, the inability of detectable amounts of exon 46(-) alpha chains to assemble into the mature membrane skeleton in vivo is probably due to a combination of decreased dimer binding affinity and increased proteolytic degradation of these mutant chains. (C) 1997 by The American Society of Hematology.

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Documento generato il 02/12/20 alle ore 14:01:52