Isoaspartate-dependent molecular switches for integrin–ligand recognition

Abstract

Formation of isoAsp in ECM proteins and its functional effects Formation of isoAsp and ECM protein damageThe formation of isoAsp residues at Asn or Asp residues in proteins is generally considered a degradation reaction as a consequence of protein aging. IsoAsp formation has been shown to occur in ECM proteins, including collagen types I and III, in fibronectin, in -crystallin and in the ECM of the mammalian brain (Lanthier and Desrosiers, 2004;Lindner and Helliger, 2001; Reissner and Aswad, SummaryIntegrins are cell-adhesion receptors that mediate cell-extracellular-matrix (ECM) and cell-cell interactions by recognizing specific ligands. Recent studies have shown that the formation of isoaspartyl residues (isoAsp) in integrin ligands by asparagine deamidation or aspartate isomerization could represent a mechanism for the regulation of integrin-ligand recognition. This spontaneous posttranslational modification, which might occur in aged proteins of the ECM, changes the length of the peptide bond and, in the case of asparagine, also of the charge. Although these changes typically have negative effects on protein function, recent studies suggested that isoAsp formation at certain Asn-Gly-Arg (NGR) sites in ECM proteins have a gain-of-function effect, because the resulting isoAsp-Gly-Arg (isoDGR) sequence can mimic Arg-Gly-Asp (RGD), a well-known integrin-binding motif. Substantial experimental evidence suggests that the NGR-to-isoDGR transition can occur in vitro in natural proteins and in drugs containing this motif, thereby promoting integrin recognition and cell adhesion. In this Commentary, we review these studies and discuss the potential effects that isoAsp formation at NGR, DGR and RGD sites might have in the recognition of integrins by natural ligands and by drugs that contain these motifs, as well as their potential biological and pharmacological implications.

Physiological, pathological, and structural implications of non-enzymatic protein–protein interactions of the multifunctional human transglutaminase 2

“…Integrin b1 and b3 contact the N-terminal domain of TG2, which contains a DGR motif. An aspartate residue in the DGR motif has been reported to undergo posttranslational modification to form an iso-DGR motif that mimics a well-known integrin binding RGD motif [168]. Syndecan-4 targets the 208-217 AA ID region, which contains several phosphorylation sites.…”

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

“…After washing and blocking with 3% BSA-DPBS, the plates were seeded with HaCaT, EA.hy926, and T98G cells diluted in 0.1% BSA-DMEM (40,000 cells/well) and left to adhere for 3 h at 37°C. Adherent cells were fixed and stained with crystal violet as described (14), and adhesion was evaluated as adsorbance at 570 nm. For each treatment condition, cell spreading was evaluated comparing cell area in different microscopy fields.…”

The protective role of protein L-isoaspartyl (D-aspartate)O-methyltransferase for maintenance of mitochondrial morphology in A549 cell

“…As molecular switches, formation of isoAsp residues in integrin ligands by Asn deamidation or Asp dehydration could participate in regulation of integrin signaling via the mechanism of increased binding activity. [50] Furthermore, recent study demonstrated that epithelial mesenchymal transition (EMT) occurred through integrin signaling in association with TGF-β signaling. [51] The increasing amounts of evidence for EMT in pathology of IPF and COPD are documented.…”