Chronoregulation by Asparagine Deamidation

Abstract

Every asparagine in every protein undergoes nonenzymatic deamidation to aspartate or isoaspartate at a rate determined by the surrounding protein structure and cellular environment. Under physiologic conditions, the deamidation half-life of individual asparagines in proteins is proposed to range from less than a day to several centuries. More than 200 proteins have been shown to undergo deamidation to a meaningful degree, and modeling predicts that hundreds more undergo deamidation at rates that have the potential to be of biological consequence. Because deamidation converts an asparagine into an aspartate or isoaspartate, it introduces a negative charge into a protein and results in the isomerization of a residue. Therefore, deamidation has the potential to change protein function. Additionally, deamidation is thought to render some proteins more susceptible to degradation. In most instances in which asparagine deamidation has been identified in vivo, it is involved in pathology. Hence, deamidation has been viewed primarily as a form of protein damage. However, the pervasiveness and evolutionary persistence of these unstable asparagines suggest that they may have a beneficial role. Notably, the change of even a single neighboring amino acid can have a marked effect on the rate of deamidation of an asparagine. Therefore, the underlying rate of deamidation of any asparagine is genetically programmable. This characteristic, combined with the wide range of deamidation rates that can be programmed, imparts to asparagines the potential to serve as molecular timers that regulate protein function and stability.

Oxidation-induced Structural Changes of Ceruloplasmin Foster NGR Motif Deamidation That Promotes Integrin Binding and Signaling

“…This reaction can occur both in vitro, e.g., during protein storage, and in vivo during protein aging (1). The rate of Asn deamidation is determined by several factors, including protein sequence and secondary/tertiary structure that, juxtaposing Asn to specific functional groups, can inhibit or accelerate the reaction (1,2).…”

“…These modifications can alter protein function and stability and render the proteins more susceptible to degradation (1). Therefore, Asn deamidation has been viewed as a sort of molecular timer that marks the spontaneous protein aging (1,3). In vivo, Asn deamidation has been observed to occur in pathological conditions associated with oxidative stress (4 -7).…”

“…Asn deamidation has been mostly considered as a proteindamaging reaction because it introduces negative charges into a protein and, in the case of isoAsp formation, causes a change in the peptide backbone length (1). These modifications can alter protein function and stability and render the proteins more susceptible to degradation (1). Therefore, Asn deamidation has been viewed as a sort of molecular timer that marks the spontaneous protein aging (1,3).…”

“…Other elements that affect Asn deamidation are related to the environment like pH, ionic strength, and temperature (1). Asn deamidation has been mostly considered as a proteindamaging reaction because it introduces negative charges into a protein and, in the case of isoAsp formation, causes a change in the peptide backbone length (1). These modifications can alter protein function and stability and render the proteins more susceptible to degradation (1).…”

“…For example, the presence of a glycine residue following Asn accelerates the deamidation reaction (3). Other elements that affect Asn deamidation are related to the environment like pH, ionic strength, and temperature (1). Asn deamidation has been mostly considered as a proteindamaging reaction because it introduces negative charges into a protein and, in the case of isoAsp formation, causes a change in the peptide backbone length (1).…”