title: Isoaspartate-dependent molecular switches for integrin-ligand recognition.
abstract: 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 post-translational 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.
authors.affiliation: Division of Molecular Oncology and IIT Network Research Unit of Molecular Neuroscience, San Raffaele Scientific Institute, via Olgettina 58, 20132 Milan, Italy. corti.angelo@hsr.it
authors.forename: Angelo
authors.initials: A
authors.lastname: Corti
authors.forename: Flavio
authors.initials: F
authors.lastname: Curnis
mesh_terms: D000818:Animals; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000235:genetics / Q000378:metabolism*; D026581:Isoaspartic Acid / Q000737:chemistry / Q000378:metabolism*; D008024:Ligands; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding
chemical_list: D016023:Integrins; D026581:Isoaspartic Acid; D008024:Ligands; D009842:Oligopeptides