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 journalArticle

131 Citations (Scopus)

Abstract

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
Volume281
Issue number47
DOIs
Publication statusPublished - Nov 24 2006

Fingerprint

Isoaspartic Acid
Fibronectins
Binding Sites
Integrins
Cell adhesion
Methyltransferases
NGR peptide
Cell Adhesion
Proteins
Extracellular Matrix Proteins
Asparagine
Endothelial cells
Isomerization
Aspartic Acid
Extracellular Matrix
Tumors
Clocks
Endothelial Cells
Aging of materials
Chemical activation

ASJC Scopus subject areas

  • Biochemistry

Cite this

Spontaneous formation of L-isoaspartate and gain of function in fibronectin. / Curnis, Flavio; Longhi, Renato; Crippa, Luca; Cattaneo, Angela; Dondossola, Eleonora; Bachi, Angela; Corti, Angelo.

In: Journal of Biological Chemistry, Vol. 281, No. 47, 24.11.2006, p. 36466-36476.

Research output: Contribution to journalArticle

Curnis, Flavio ; Longhi, Renato ; Crippa, Luca ; Cattaneo, Angela ; Dondossola, Eleonora ; Bachi, Angela ; Corti, Angelo. / Spontaneous formation of L-isoaspartate and gain of function in fibronectin. In: Journal of Biological Chemistry. 2006 ; Vol. 281, No. 47. pp. 36466-36476.
@article{4973c820c5d04c69b949106d0fec1aaf,
title = "Spontaneous formation of L-isoaspartate and gain of function in fibronectin",
abstract = "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.",
author = "Flavio Curnis and Renato Longhi and Luca Crippa and Angela Cattaneo and Eleonora Dondossola and Angela Bachi and Angelo Corti",
year = "2006",
month = "11",
day = "24",
doi = "10.1074/jbc.M604812200",
language = "English",
volume = "281",
pages = "36466--36476",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "47",

}

TY - JOUR

T1 - Spontaneous formation of L-isoaspartate and gain of function in fibronectin

AU - Curnis, Flavio

AU - Longhi, Renato

AU - Crippa, Luca

AU - Cattaneo, Angela

AU - Dondossola, Eleonora

AU - Bachi, Angela

AU - Corti, Angelo

PY - 2006/11/24

Y1 - 2006/11/24

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=33846020967&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33846020967&partnerID=8YFLogxK

U2 - 10.1074/jbc.M604812200

DO - 10.1074/jbc.M604812200

M3 - Article

VL - 281

SP - 36466

EP - 36476

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 47

ER -