Alteration of an intersubunit contact in hemoglobin variants: comparative study of modifications at position alpha 126 Asp (H9).
Four human hemoglobin variants have already been described at position alpha 126 (H9), which is normally occupied by an aspartate: Hb Montefiore (-->Tyr), Hb Tarrant (-->Asn), Hb Fukutomi (-->Val), Hb Sassari (-->His). An additional variant, Hb West One (alpha 126 (H9) Asp-->Gly) is herein described. Aspartate alpha 126 (H9) is involved in a set of hydrogen bonds and salt bridges located at the C-terminal portion of the alpha-chains and of the C-helix of the beta-chains, which are broken in the oxy conformer, providing one of the most important sources of the difference in free energy between the T- and R-state in hemoglobin. A comparative study of four of these alpha 126 Hb variants is presented. An identical degree of alteration of the oxygen binding properties (increased oxygen affinity and decreased cooperativity) was found in all cases, when measured under standard experimental conditions (pH 7.2, 0.1 M NaCl). In contrast, the effect of L345 (a derivative of bezafibrate, which is a specific alpha-chain binding effector) on oxygen binding to Hb differed from one variant to another. When a bulky Tyr or His residue occupied the alpha 126 (H9) position, little effect of L345 was observed. Conversely, when this position was occupied by a residue of smaller size (Gly or Asn), normal heterotropic effects were observed. Molecular graphic modelling indicates that two classes of three-dimensional structure modifications may occur.
Kister
J
J
Inserm U299, hôpital de Bicêtre, Le Kremlin Bicêtre, France.
Griffon
N
N
Henthorn
J S
JS
Marden
M C
MC
Poyart
C
C
Papassotiriou
I
I
Promé
D
D
Galactéros
F
F
Davies
S C
SC
Wajcman
H
H
D000495:Allosteric Site / Q000187:drug effects; D001224:Aspartic Acid; D006455:Hemoglobins, Abnormal / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D008958:Models, Molecular; D009154:Mutation; D010100:Oxygen / Q000378:metabolism; D010671:Phenylurea Compounds / Q000494:pharmacology; D011485:Protein Binding
D006455:Hemoglobins, Abnormal; D010671:Phenylurea Compounds; C064071:L 345; D001224:Aspartic Acid; D010100:Oxygen