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J. Biol. Chem., Vol. 281, Issue 47, 36466-36476, November 24, 2006

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Spontaneous Formation of L-Isoaspartate and Gain of Function in Fibronectin^*

Flavio Curnis, Renato Longhi, Luca Crippa, Angela Cattaneo, Eleonora Dondossola, Angela Bachi, and Angelo Corti¹

From the Department of Oncology, Cancer Immunotherapy and Gene Therapy Program and Italian Institute of Technology Network Research Unit of Molecular Neuroscience, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, and Istituto di Chimica del Riconoscimento Molecolare, Consiglio Nazionale delle Ricerche, Via M. Bianco 9, 20131 Milan, Italy

Isoaspartate formation in extracellular matrix proteins, by aspartate isomerization or asparagine deamidation, is generally viewed as a degradation reaction occurring in vivo during tissue aging. For instance, non-enzymatic isoaspartate formation at RGD-integrin binding sites causes loss of cell adhesion sites, which in turn can be enzymatically "repaired" to RGD by protein-L-isoAsp-O-methyltransferase. We show here that isoaspartate formation is also a mechanism for extracellular matrix activation. In particular, we show that deamidation of Asn²⁶³ at the Asn-Gly-Arg (NGR) site in fibronectin N-terminal region generates an _v3-integrin binding site containing the L-isoDGR sequence, which is enzymatically "deactivated" to DGR by protein-L-isoAsp-O-methyltransferase. Furthermore, rapid NGR-to-isoDGR sequence transition in fibronectin fragments generates _v3 antagonists (named "isonectins") that competitively bind RGD binding sites and inhibit endothelial cell adhesion, proliferation, and tumor growth. Time-dependent generation of isoDGR may represent a sort of molecular clock for activating latent integrin binding sites in proteins.

Received for publication, May 18, 2006 , and in revised form, September 15, 2006.

^* This work was supported in part by Associazione Italiana per la Ricerca sul Cancro. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 39-02-26434802; Fax: 39-02-26434786; E-mail: corti.angelo{at}hsr.it.

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