Spontaneous Cleavage at Glu and Gln Residues in Long-Lived Proteins

Abstract

Long-lived proteins (LLPs) are prone to deterioration with time, and one prominent breakdown process is the scission of peptide bonds. These cleavages can either be enzymatic or spontaneous. In this study, human lens proteins were examined and many were found to have been cleaved on the C-terminal side of Glu and Gln residues. Such cleavages could be reproduced experimentally by in vitro incubation of Glu- or Gln-containing peptides at physiological pHs. Spontaneous cleavage was dependent on pH and amino acid sequence. These model peptide studies suggested that the mechanism involves a cyclic intermediate and is therefore analogous to that characterized for cleavage of peptide bonds adjacent to Asp and Asn residues. An increased amount of some Glu/Gln cleaved peptides in the insoluble fraction of human lenses suggests that cleavage may act to destabilize proteins. Spontaneous cleavage at Glu and Gln, as well as recently described cross-linking at these residues, can therefore be added to the similar processes affecting long-lived proteins that have already been documented for Asn and Asp residues.

Kingdom-specific lipid unsaturation shapes up sequence evolution in membrane arm subunits of eukaryotic respiratory complexes

“…4F ). Local chemistry driven cleavage of peptide bonds after N and Q have been reported for multiple proteins 61–65 . At-A1 trans-IMM helix present in Ch-A1 contains both N and Q at the C-terminus ( Fig.…”

Imaging Cataract-Specific Peptides in Human Lenses

“…Similarly, the formation of γD-crystallin 162–173 corresponds to cleavage at Asn 161. Spontaneous cleavage at Asp and Asn through a succinimide intermediate [ 26 ] or Glu or Gln through a glutarimide [ 27 ] is a well-known mechanism for protein cleavage and this process is also coupled with deamidation, isomerization, and racemization of Asn or Gln residues [ 26 ]. These mechanisms explain truncation, deamidation and isomerization at many different Asn, Asp, Gln and Glu residues throughout the lens proteome, especially the ones that are followed by small, flexible residues such as glycine [ 26 , 28 , 29 ].…”

Progesterone inhibits endometrial cancer growth by inhibiting glutamine metabolism through ASCT2

“…Gln is metabolized into α-ketoglutaric acid and enters the Krebs cycle to provide energy for cells and precursors for macromolecule synthesis. Gln can also be broken down to glutamate, directly converted or reconverted to other amino acids, or be used as a nitrogen source for purine and pyrimidine synthesis and the hexosamine biosynthesis pathway [ 15 ]. The increased glutamine demand by tumor cells enhances glutamine metabolism to compensate for the intermediates required by the tricarboxylic acid cycle, which satisfies the energy requirements for biomolecular synthesis and redox homeostasis of tumor cells and promotes glutamine-dependent tumor cell growth [ 16 ].…”