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J. Biol. Chem., Vol. 280, Issue 25, 23675-23683, June 24, 2005

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Identification of a Novel Recognition Sequence for Fibronectin within the NH₂-terminal -Sandwich Domain of Tissue Transglutaminase^*

Jun Hang, Evgeny A. Zemskov, Laszlo Lorand, and Alexey M. Belkin¶

From the Department of Biochemistry and Molecular Biology and Greenebaum Cancer Center, University of Maryland, Baltimore, Maryland 21201 and Department of Cell and Molecular Biology, Northwestern University Feinberg Medical School, Chicago, Illinois 61601

Tissue transglutaminase belongs to the multigene transglutaminase family of Ca²⁺-dependent protein cross-linking enzymes. Unlike other transglutaminases, it is involved in cell-matrix interactions and serves as an adhesion co-receptor for fibronectin. Previous work established that the fibronectin-binding motif(s) is located within the NH₂-terminal proteolytic fragment of the protein consisting of residues 1–272. Here we identify a novel fibronectin recognition site within this sequence of tissue transglutaminase. Substitution of individual domains of tissue transglutaminase with those from homologous factor XIIIA showed that the major fibronectin-binding site is present within the first -sandwich domain of the protein. Experiments with deletion mutants of the first domain revealed that amino acids 81–140 of tissue transglutaminase are involved in fibronectin binding. Using synthetic peptides encompassing this region, we found that the peptide ⁸⁸WTATVVDQQDCTLSLQLTT¹⁰⁶ inhibited the interaction of tissue transglutaminase with fibronectin and decreased transglutaminase-dependent cell adhesion and spreading. In the three-dimensional structure of the first domain, amino acids 88–106 comprise an extended hairpin formed by antiparallel strands 5 and 6. Mutations of Asp⁹⁴ and Asp⁹⁷ within the 5/6 hairpin to Ala significantly reduced the affinity of tissue transglutaminase for fibronectin, indicating that these residues are critical for fibronectin binding. Identification of the fibronectin-binding site on tissue transglutaminase will help to dissect the role of this protein in cell-matrix interactions.

Received for publication, March 25, 2005 , and in revised form, April 20, 2005.

^* This work was supported by National Institutes of Health Grants GM62895 (to A. M. B.) and HL02212 (to L. L). 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.

^¶ To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, University of Maryland School of Medicine, 15601 Crabbs Branch Way, Rockville, MD 20855. Tel.: 301-738-0725; Fax: 301-738-0740; E-mail: abelk001{at}umaryland.edu.

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