Structure of the EF corner favors deamidation of asparaginyl residues in hemoglobin: the example of Hb La Roche-sur-Yon [ β81 (EF5) Leu → His

Abstract

Some abnormal hemoglobins constitute models which allow one to evaluate the structural requirements for post-translational modifications in proteins, such as deamidation. Hb La Roche-sur-Yon [ β81 (EF5) Leu → His] is an unstable hemoglobin variant displaying a moderately increased oxygen affinity. About half of the abnormal hemoglobin, in addition to the substitution at position β81, carries a deamidation of the neighboring asparagine residue, β80(EF4). The histidine at position β81 cannot fit into the small hydrophobic pocket which normally accomodates the leucine residue. This structural change opens the heme pocket and modifies the general conformation of the EF segment, thus explaining the increase in oxygen affinity and the achievement of a three-dimensional structure favoring asparagine deamidation. Histidine ß81 could also act as a catalyst in the deamidation reaction. Deamidation has already been reported for two other variants of the EF corner, Hb Providence [ ß82 (EF6) Lys → Asn] and Hb J Singapore [ α79 (EF8) Ala → Gly]. In all these cases it seems that a histidine may catalyze the deamidation of the asparagine residues and that disturbing the folding of the EF corner will provide an extra flexibility favoring the reaction.