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J. Biol. Chem., Vol. 281, Issue 19, 13396-13403, May 12, 2006

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The Structure of the Extracellular Domain of Triggering Receptor Expressed on Myeloid Cells Like Transcript-1 and Evidence for a Naturally Occurring Soluble Fragment^*

James L. Gattis, A. Valance Washington, Maia M. Chisholm, Laura Quigley, Agnieszka Szyk, Daniel W. McVicar, and Jacek Lubkowski¹

From the Macromolecular Crystallography Laboratory and the Laboratory of Experimental Immunology, NCI, National Institutes of Health, Frederick, Maryland 21702

Triggering receptor expressed on myeloid cells like transcript-1 (TLT-1) is an abundant platelet-specific, type I transmembrane receptor. The extracellular fragment of TLT-1 consists of a single, immunoglobulin-like domain connected to the platelet cell membrane by a linker region called the stalk. Here we present evidence that a soluble fragment of the TLT-1 extracellular domain is found in serum of humans and mice and that an isoform of similar mass is released from platelets following activation with thrombin. We also report the crystal structure of the immunoglobulin domain of TLT-1 determined at the resolution of 1.19 Å. The structure of TLT-1 is similar to other immunoglobulin-like variable domains, particularly those of triggering receptor expressed on myeloid cells-1 (TREM-1), the natural killer cell-activating receptor NKp44, and the polymeric immunoglobulin receptor. Particularly interesting is a 17-amino acid segment of TLT-1, homologous to a fragment of murine TREM-1, which, in turn, showed activity in blocking the TREM-1-mediated inflammatory responses in mice. Structural similarity to TREM-1 and polymeric immunoglobulin receptor, and evidence for a naturally occurring soluble fragment of the TLT-1 extracellular domain, suggest that this immunoglobulin-like domain autonomously plays an as yet unidentified, functional role.

Received for publication, January 17, 2006 , and in revised form, February 24, 2006.

The atomic coordinates and structure factors (code 2FRG) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract W-31-109-Eng-38. The project was supported by the Intramural Research Program of NCI, National Institutes of Health (NIH), Center for Cancer Research. 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: NCI, NIH, Fort Detrick, 7th St., Bldg. 539, P. O. Box B, Rm. 150, Frederick, MD 21702. Tel.: 301-846-5494; Fax: 301-846-7101; E-mail jacek{at}ncifcrf.gov.

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