Spontaneous formation of L-isoaspartate and gain of function in fibronectin

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

Research output: Contribution to journalArticlepeer-review


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 α vβ3-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 αvβ 3 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.

Original languageEnglish
Pages (from-to)36466-36476
Number of pages11
JournalJournal of Biological Chemistry
Issue number47
Publication statusPublished - Nov 24 2006

ASJC Scopus subject areas

  • Biochemistry


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