The high resolution crystal structure of deoxyhemoglobin S

Harrington, Daniel J.; Adachi, K.; Royer, William E.

doi:10.1006/jmbi.1997.1253

Cited by 159 publications

(221 citation statements)

References 27 publications

(24 reference statements)

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“…By and large, the fiber models agree with the solution polymerization experiments of mutant hemoglobins in that polymerizationsensitive mutations are usually located in fiber contact regions (27). However, the models present an approximate description of the HbS fiber that are limited to the identity of the contact residues and totally lack information on the hierarchy of interactions or additive or synergistic effect of two or more contact residues (4,26,27). Furthermore, the models project a static view of the contact sites and do not provide any clues about the influence of flexibility or dynamics of a given contact region on fiber assembly.…”

supporting

confidence: 54%

“…Deoxygenated sickle hemoglobin (HbS) polymerizes into long helical fibers that are believed to be responsible for the pathophysiology of the sickle cell disease. The knowledge gleaned so far from structural analysis of HbS crystal (2)(3)(4), solution polymerization studies of natural variants or engineered mutant hemoglobins (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24), and electron microscopic studies (25) have led to a 14-stranded model of the fiber (26,27). These strands appear as seven double strands of the type found in HbS crystals, albeit with a slight twist caused by fiber packing.…”

mentioning

confidence: 99%

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Linkage of Interactions in Sickle Hemoglobin Fiber Assembly

Sudha

Anantharaman

Sivaram

et al. 2004

Journal of Biological Chemistry

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The AB and GH regions of the ␣-chain are located in spatial proximity and contain a cluster of intermolecular contact residues of the sickle hemoglobin (HbS) fiber. We have examined the role of dynamics of AB/GH region on HbS polymerization through simultaneous replacement of non-contact Ala 19 and Ala 21 of the AB corner with more flexible Gly or rigid ␣-aminoisobutyric acid (Aib) residues. The polymerization behavior of HbS with Aib substitutions was similar to the native HbS. In contrast, Gly substitutions inhibited HbS polymerization. Molecular dynamics simulation studies of ␣-chains indicated that coordinated motion of AB and GH region residues present in native (Ala) as well as in Aib mutant was disrupted in the Gly mutant. The inhibitory effect due to Gly substitutions was further explored in triple mutants that included mutation of an inter-doublestrand contact (␣Asn 78 3 His or Gln) at the EF corner. Although the inhibitory effect of Gly substitutions in the triple mutant was unaffected in the presence of ␣Gln 78 , His at this site almost abrogated its inhibitory potential. The polymerization studies of point mutants (␣Gln 78 3 His) indicated that the inhibitory effect due to Gly substitutions in the triple mutant was synergistically compensated for by the polymerization-enhancing activity of His 78 . Similar synergistic coupling, between ␣His 78and an intra-double-strand contact point (␣16) mutation located in the AB region, was also observed. Thus, two conclusions are made: (i) Gly mutations at the AB corner inhibit HbS polymerization by perturbing the dynamics of the AB/GH region, and (ii) perturbations of AB region (through changes in dynamics of the AB/GH region or abolition of a specific fiber contact site) that influence HbS polymerization do so in concert with ␣78 site at the EF corner. The overall results provide insights about the interaction-linkage between distant regions of the HbS tetramer in fiber assembly.Sickle cell anemia arises because of a point mutation at the sixth position of the ␤-chain (␤Glu 6 3 Val) in the hemoglobin (Hb) 1 molecule (1). Deoxygenated sickle hemoglobin (HbS) polymerizes into long helical fibers that are believed to be responsible for the pathophysiology of the sickle cell disease. The knowledge gleaned so far from structural analysis of HbS crystal (2-4), solution polymerization studies of natural variants or engineered mutant hemoglobins (5-24), and electron microscopic studies (25) have led to a 14-stranded model of the fiber (26, 27). These strands appear as seven double strands of the type found in HbS crystals, albeit with a slight twist caused by fiber packing. The models specify several amino acid residues from both ␣-and ␤-chains that participate in inter-or intradouble-strand contacts stabilizing the fiber structure. By and large, the fiber models agree with the solution polymerization experiments of mutant hemoglobins in that polymerizationsensitive mutations are usually located in fiber contact regions (27). However, the models present an approximate...

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supporting

confidence: 54%

mentioning

confidence: 99%

Linkage of Interactions in Sickle Hemoglobin Fiber Assembly

Sudha

Anantharaman

Sivaram

et al. 2004

Journal of Biological Chemistry

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“…The structure and function of hemoglobin were elucidated by Max Perutz (Perutz et al, 1960) and has since been understood in more detail with improved structural resolution (Harrington et al, 1997;Padlan and Love, 1985). SCD is an autosomal recessive genetic disease caused by a single point mutation in the β-globin subunit of hemoglobin that changes the negatively charged glutamic acid residue to a hydrophobic valine residue, resulting in noncovalent polymerization and double-strand formation under lowoxygen conditions.…”

Section: Introductionmentioning

confidence: 99%

Visualizing red blood cell sickling and the effects of inhibition of sphingosine kinase 1 using soft X-ray tomography

Darrow

Zhang

Cinquin

et al. 2016

Journal of Cell Science

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Sickle cell disease is a destructive genetic disorder characterized by the formation of fibrils of deoxygenated hemoglobin, leading to the red blood cell (RBC) morphology changes that underlie the clinical manifestations of this disease. Using cryogenic soft X-ray tomography (SXT), we characterized the morphology of sickled RBCs in terms of volume and the number of protrusions per cell. We were able to identify statistically a relationship between the number of protrusions and the volume of the cell, which is known to correlate to the severity of sickling. This structural polymorphism allows for the classification of the stages of the sickling process. Recent studies have shown that elevated sphingosine kinase 1 (Sphk1)-mediated sphingosine 1-phosphate production contributes to sickling. Here, we further demonstrate that compound 5C, an inhibitor of Sphk1, has anti-sickling properties. Additionally, the variation in cellular morphology upon treatment suggests that this drug acts to delay the sickling process. SXT is an effective tool that can be used to identify the morphology of the sickling process and assess the effectiveness of potential therapeutics.

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“…Recently, the crystal structure o f deoxyHbS has also been refined at 2.05 A resolution [10]. These studies have shown that the Wishner-Love double strand o f Hb tetramers is the basic building block o f the intracellular sickle cell fibre (figure 1.3).…”

Section: Structure Of Hbs Moleculementioning

confidence: 99%