Sequence and structure determinants of the nonenzymatic deamidation of asparagine and glutamine residues in proteins

Abstract

The rates of deamidation of Asn and Gln residues in peptides and proteins depend upon both the identity of other nearby amino acid residues, some of which can catalyze the deamidation reaction of the Asn and Gln side chains, and upon polypeptide conformation. Proximal amino acids can be contiguous in sequence or brought close to Asn or Gln side chains by higher order structure of the protein. Local polypeptide conformation can stabilize the oxyanion transition state of the deamidation reaction and also enable deamidation through the beta-aspartyl shift mechanism. In this paper, the environments of Asn and Gln residues in known protein structures are examined to determine the configuration and identity of groups which participate in deamidation reactions. Sequence information is also analyzed and shown to support evolutionary selection against the occurrence of certain potentially catalytic amino acids adjacent to Asn and Gln in proteins. This negative selection supports a functional role for deamidation in those non-mutant proteins in which it occurs.

Quantitative N-linked Glycoproteomics of Myocardial Ischemia and Reperfusion Injury Reveals Early Remodeling in the Extracellular Environment

“…The majority of these were located with either Gly (N-G) or Ser (N-S) at the ϩ1 position. N-G and N-S are common in vivo deamidation motifs (41,43). Furthermore, since deglycosylation most likely increases the efficiency of proteolytic digestion (particularly where the glycan attachment site is close to the protease cleavage site), it is probable that false positives have been under-estimated in the current study and must contribute very significantly in other studies that have not employed such controls.…”

Activation of an Asp‐124→Asn mutant of haloalkane dehalogenase by hydrolytic deamidation of asparagine

“…Edman degradation stops at isoaspartate, and no such stops were encountered. Furthermore, deamidation with a cyclic imide as intermediate is most rapid with asparagines located on the N-terminal side of glycine residues; it has never been found with an asparagine preceding a tryptophan, as present in haloalkane dehalogenase [17]. The rate of deamidation of Asn-124 is also much faster than deamidation rates observed in other proteins, since it can be measured within hours instead of days or years [16].…”

Mitochondria: A mirror into cellular dysfunction in heart disease

“…White et al however, showed both non-deamidated and deamidated forms, suggesting that the modification was not related to sample processing. In addition, it has also been suggested that deamidation at Asn-Gly and Asn-Ser motifs are biologically relevant [161,162], which corresponds with the observed deamidation to a B-crystalline (Asn 146 -Gly 147 ) [160] and may explain the proteolysis of MLC-2 between Asn 13 and Ser 14 [88]. Whilst it appears that myofilament and cytosolic proteins are deamidated and preferentially degraded with I/R injury, the role of deamidation in the mitochondria during pathology has not yet been determined.…”