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J Biol Chem, Vol. 273, Issue 19, 11423-11428, May 8, 1998

Identification of the Ligand Binding Site for the Integrin ₉₁ in the Third Fibronectin Type III Repeat of Tenascin-C

Yasuyuki Yokosaki^§, Nariaki Matsuura, Shigeki Higashiyama^**, Isao Murakami^§, Masanobu Obara, Michio Yamakido^§§, Norikazu Shigeto, John Chen^¶¶, and Dean Sheppard^¶¶

From the Departments of  Internal Medicine and ^§ Laboratory Medicine, National Hiroshima Hospital, 513 Jike, Saijoh, Higashi-Hiroshima 739-0041,  Department of Pathology, School of Allied Health Sciences, ^** Department of Biochemistry, Faculty of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871,  Department of Developmental Science, Faculty of Science, Hiroshima University, 1-1 Kagamiyama, Saijoh, Higashi-Hiroshima 739-8526, ^§§ Department of Internal Medicine II, School of Medicine, Hiroshima University, 1-2-3 Kasumi, Minamiku, Hiroshima 734-8551, Japan, and the ^¶¶ Lung Biology Center, Department of Medicine, University of California, San Francisco, California 94143

The integrin ₉ subunit forms a single heterodimer, ₉₁ that mediates cell adhesion to a site within the third fibronectin type III repeat of tenascin-C (TNfn3). In contrast to at least 3 other integrins that bind to this region of tenascin-C, ₉₁ does not recognize the common integrin recognition motif, Arg-Gly-Asp (RGD). In this report, we have used substitution mutagenesis to identify a unique ligand recognition sequence in TNfn3. We introduced mutations substituting alanine for each of the acidic residues in or adjacent to each of the exposed loops predicted from the solved crystal structure. Most of these mutations had little or no effect on adhesion of ₉-transfected SW480 colon carcinoma cells, but mutations of either of two acidic residues in the B-C loop region markedly reduced attachment of these cells. In contrast, cells expressing the integrin _v3, previously reported to bind to the RGD sequence in the adjacent F-G loop, attached to all mutant fragments except one in which the RGD site was mutated to RAA. The peptide, AEIDGIEL, based on the sequence of human tenascin-C in this region blocked the binding of ₉-transfected cells, but not ₃-transfected cells to wild type TNfn3. This sequence contains a tripeptide, IDG, homologous to the sequences LDV, IDA, and LDA in fibronectin and IDS in VCAM-1 recognized by the closely related integrin ₄₁. These findings support the idea that this tripeptide motif serves as a ligand binding site for the ₄/₉ subfamily of integrins.

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Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.

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