期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 277, 期 34, 页码 30502-30507出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M205314200
关键词
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Proteins are vulnerable to spontaneous, covalent modifications that may result in alterations to structure and function. Asparagines are particularly labile, able to undergo deamidation through the formation of a succinimide intermediate to produce either aspartate or isoaspartate residues. Although aspartates cannot undergo deamidation they can form a succinimide and result in the same products. Isoaspartyls are the principal product of succinimide hydrolysis, accounting for 65-85% of the emerging residues. The variability in the ratio of products emerging from succinimide hydrolysis suggests the ability of protein structure to influence succinimide outcome. In the H15D histidine-containing protein (HPr), phosphorylation of the active site aspartate catalyzes the formation of a cyclic intermediate. Resolution of this species is exclusively to aspartate residues, suggestive of either a succinimide with restrained hydrolysis, or an isoimide, from which aspartyl residues are the only possible product. Deletion of the C-terminal residue of this protein does not influence the ability for phosphorylation or ring formation, but it does allow for isoaspartyl formation, verifying a succinimide as the cyclic intermediate in H15D HPr. Isoaspartyl formation in H15D Delta85 is rationalized to occur as a consequence of elimination of steric restrictions imposed by the C terminus on the main-chain carbonyl of the succinimide, the required point of nucleophilic attack of a water molecule for isoaspartyl formation. This is the first reported demonstration of the influence of protein structure on the products emerging from succinimide hydrolysis.
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