Isoaspartate-dependent molecular switches for integrin-ligand recognition
Isoaspartate-dependent molecular switches for integrin-ligand recognition
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DOI：
10.1242/jcs.077172
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发表时间：
2011-02-15
影响因子：
4
通讯作者：
Curnis, Flavio
中科院分区：
文献类型：
--
作者：
Corti, Angelo;Curnis, Flavio
整合素是一种细胞黏附受体，通过识别特定的配体来调节细胞-细胞外-基质(ECM)和细胞-细胞之间的相互作用。最近的研究表明，天冬酰胺脱酰胺或天冬氨酸异构化在整合素配体上形成的异天冬氨酸残基(IsAsp)可能是整合素配体识别的调节机制。这种自发的翻译后修饰可能发生在细胞外基质的老化蛋白质中，改变了肽键的长度，对于天冬酰胺来说，也改变了电荷的长度。尽管这些变化通常会对蛋白质功能产生负面影响，但最近的研究表明，ECM蛋白质中某些ASN-Gly-Arg(NGR)位点上的isAsp形成具有功能增益效应，因为得到的isAsp-Gly-Arg(IsoDGR)序列可以模拟已知的整合素结合基序Arg-Gly-Asp(RGD)。大量实验证据表明，在体外，天然蛋白质和含有该基序的药物中可以发生从NGR到等DGR的转变，从而促进整合素识别和细胞黏附。在这篇评论中，我们回顾了这些研究，并讨论了在NGR、DGR和RGD位点形成isAsp对天然配体和含有这些基序的药物识别整合素的潜在影响，以及它们潜在的生物学和药理学意义。
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.