Molecular and functional changes in spectrin from patients with hereditary pyropoikilocytosis.

Knowles, William J.; Morrow, Jon S.; Speicher, David W.; Zarkowsky, Harold S.; Mohandas, Narla; Mentzer, WC; Shohet, Stephen B.; Marchesi, V.

doi:10.1172/jci110942

Cited by 87 publications

(47 citation statements)

References 29 publications

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“…They found that the :-subunit of spectrin extracted from HE erythrocytes was resistant to trypsin digestion, as compared with controls. A second (3- (14)(15)(16). Polymorphism of the a-II domain of spectrin has also been detected in the normal population by limited tryptic digestion (14,17).…”

Section: Introductionmentioning

confidence: 99%

A molecular defect of spectrin in a subset of patients with hereditary elliptocytosis. Alterations in the alpha-subunit domain involved in spectrin self-association.

Lawler¹,

Liu²,

Palek³

et al. 1984

J. Clin. Invest.

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Section: Introductionmentioning

confidence: 99%

A molecular defect of spectrin in a subset of patients with hereditary elliptocytosis. Alterations in the alpha-subunit domain involved in spectrin self-association.

Lawler¹,

Liu²,

Palek³

et al. 1984

J. Clin. Invest.

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“…The importance of spectrin in the resistance of tissues to the forces generated by muscle contraction is evident in all animals: thus for example, in the worm Caenorhabditis elegans spectrin is required to strengthen adhesion between the body wall and the muscles beneath (12, 13). By contrast, αI-spectrin is abundant in enucleate red blood cells, where it imparts to the membrane the elasticity needed to survive the rigors of circulation (7,(14)(15).The functional distinction between the spectrins of mammalian tissue and erythrocyte is reflected in their physical properties. Spectrin purified from brain (comprising mainly αII and βII polypeptides, also known as fodrin) has a stiffer and straighter appearance in the electron microscope than that of the erythrocyte (αIβI) spectrin (16)(17)(18)(19), and this difference is also reflected in their hydrodynamic properties (16,19).…”

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confidence: 99%

Thermal Stabilities of Brain Spectrin and the Constituent Repeats of Subunits

Zhang

Salomao

et al. 2006

Biochemistry

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The different genes that encode mammalian spectrins give rise to proteins differing in their apparent stiffness. To explore this, we have compared the thermal stabilities of the structural repeats of brain spectrin subunits (αII-and βII) with those of erythrocyte spectrin (αI-and βI). The unfolding transition mid-points (T m ) of the 36 αII-and βII-spectrin repeats extend between 24 and 82°C, with an average higher by some 10°C than that of the αI-and βI-spectrin repeats. This difference is reflected in the T m -s of the intact brain and erythrocyte spectrins. Two of three tandem-repeat constructs from brain spectrin showed strong cooperative coupling, with elevation of the T m of the less stable partner corresponding to coupling free energies of about −4.4 and −3.5 kcal mol −1 . The third tandem-repeat construct, by contrast, showed negligible cooperativity. Tandem-repeat mutants, in which a part of the 'linker' helix that connects the two domains was replaced by a corresponding helical segment from erythroid spectrin, showed only minor perturbation of the thermal melting profiles, without breakdown of cooperativity. Thus the linker regions, which tolerate few point-mutations without loss of cooperative function, have evidently evolved to permit conformational coupling in specified regions. The greater structural stability of the repeats in αII-and βII-spectrin may account, at least in part, for the higher rigidity of brain compared to erythrocyte spectrin.Spectrin arose in evolution with the metazoa to meet the need for structures that strengthen cell adhesions and stabilize the plasma membrane against the forces of animal movement (1). The protein also plays a part in organizing plasma membrane signalling complexes (1, 2). Spectrin occurs as an (αβ) 2 tetramer, specialized for cross-linking actin filaments to membrane constituents. Both the α and β chains are largely made up of consecutive triplehelical repeating units of about 106 amino acids (3, 4); these act in ensemble as spacers between actin-binding domains in the β-subunits at opposite ends of the tetramers, and some contain binding sites for proteins such as ankyrin or for aminophospholipids (5, 6). *Author for correspondence: Xiuli An, Red Cell Physiology Laboratory, 310 E 67 th St, New York, NY10021, Tel: 212-570-3247; Fax: 212-570-3195. xan@nybloodcenter.org. HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptThe number of spectrin genes increased during evolution with the advent of vertebrates.Invertebrates have one α-spectrin and, one β-spectrin with 16 complete triple-helical repeats and a β Heavy subunit with 30 complete triple helices. Vertebrates have four genes encoding 'conventional' β subunits (βI-IV) that have 16 complete triple helical modules, and one β Heavy subunit that has 30 triple helices (βV-spectrin) (1). Mammals have gained an additional α-spectrin by duplication of the pre-existing α-spectrin gene (7). There is now clear evidence of functional specialization of the two mammalian α-...

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“…The moderate increase of spectrin dimer in the proband 4°C extract (26%) compared to the values found in other family members could be explained by the presence in the blood of transfused cells. Until today, three congenital hemolytic disorders with poikilocytosis have been found to be related to a defective self-association of spectrin: HPP (8,17,20,26), homozygous HE 4 CS, crude spectrin extract performed at 37°C. SD, spectrin dimer isolated from spectrin tetramer after self-association process.…”

Section: Discussionmentioning

confidence: 99%

Molecular Defect of Spectrin in the Family of a Child with Congenital Hemolytic Poikilocytic Anemia

et al. 1984

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Summary PBS. ~hos~hate-buffered salineWe present the study of a black family in which the proband suffered from a severe neonatal hemolytic anemia with poikilocytosis. Both the parents, sister's, and brother's proband were clinically normal. The presence of poikilocytes in proband led to a search for a red cell membrane skeleton defect. Owing to recent improvements in the erythrocyte membrane knowledge, it is now possible to approach the diagnosis by means of biochemical evaluation of both parents, even if they are asymptomatic. So, the first time discovery of a spectrin self-association defect in both parents allowed us to suspect double inheritance of this abnormality in the proband. A complete morphological and biochemical evaluation of the family allowed us to propound the diagnosis of heterozygous type 1 hereditary elliptocytosis (HE) for both parents and the sister and the diagnosis of homozygous type I HE for the proband owing to the following reasons: slight ovalocytosis was present in both parents and the sister, cell deformability ektacytometric studies gave the same profiles of curve as those observed in patients with HE. Defective spectrin dimer self-association found in both parents was also observed in the sister and proband, associated with the same abnormal spectrin digest pattern, namely a decrease in the amount of a 80,000-dalton peptide and a corresponding increase in a 74,000-dalton peptide. However, clinical presentation of the proband was consistent either with hereditary pyropoikilocytosis or homozygous hereditary elliptocytosis; erythrocyte thermal sensitivity studies in the proband could not be conclusive because of the presence of transfused cells. Both these diagnoses are discussed in detail. Other modifications of spectrin tryptic patterns were detectable and were not related to the functional defect of spectrin since the proband's normal brother appeared homozygous for these modifications.Abbreviations HPP, hereditary pyropoikilocytosis HE, hereditary elliptocytosis PMSF, phenylmethylsulfonyl fluoride SDS, sodium dodecyl sulfate BME, B-mercaptoethanol

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Molecular and functional changes in spectrin from patients with hereditary pyropoikilocytosis.

Cited by 87 publications

References 29 publications

A molecular defect of spectrin in a subset of patients with hereditary elliptocytosis. Alterations in the alpha-subunit domain involved in spectrin self-association.

A molecular defect of spectrin in a subset of patients with hereditary elliptocytosis. Alterations in the alpha-subunit domain involved in spectrin self-association.

Thermal Stabilities of Brain Spectrin and the Constituent Repeats of Subunits

Molecular Defect of Spectrin in the Family of a Child with Congenital Hemolytic Poikilocytic Anemia

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