Isoaspartate-dependent molecular switches for integrin-ligand recognition

A. Corti, F. Curnis
2011 Journal of Cell Science  
Formation of isoAsp in ECM proteins and its functional effects Formation of isoAsp and ECM protein damage The 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,
more » ... eissner and Aswad, Summary Integrins 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.
doi:10.1242/jcs.077172 pmid:21282473 fatcat:optnmulf4rbjvkfxs7ojridjae