title: The structure of the extracellular domain of triggering receptor expressed on myeloid cells like transcript-1 and evidence for a naturally occurring soluble fragment.
abstract: 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 A. 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.
authors.affiliation: Macromolecular Crystallography Laboratory, NCI, National Institutes of Health, Frederick, Maryland 21702.
authors.forename: James L
authors.initials: JL
authors.lastname: Gattis
authors.affiliation: Laboratory of Experimental Immunology, NCI, National Institutes of Health, Frederick, Maryland 21702.
authors.forename: A Valance
authors.initials: AV
authors.lastname: Washington
authors.affiliation: Laboratory of Experimental Immunology, NCI, National Institutes of Health, Frederick, Maryland 21702.
authors.forename: Maia M
authors.initials: MM
authors.lastname: Chisholm
authors.affiliation: Laboratory of Experimental Immunology, NCI, National Institutes of Health, Frederick, Maryland 21702.
authors.forename: Laura
authors.initials: L
authors.lastname: Quigley
authors.affiliation: Macromolecular Crystallography Laboratory, NCI, National Institutes of Health, Frederick, Maryland 21702.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Szyk
authors.affiliation: Laboratory of Experimental Immunology, NCI, National Institutes of Health, Frederick, Maryland 21702.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: McVicar
authors.affiliation: Macromolecular Crystallography Laboratory, NCI, National Institutes of Health, Frederick, Maryland 21702. Electronic address: jacek@ncifcrf.gov.
authors.forename: Jacek
authors.initials: J
authors.lastname: Lubkowski
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D002460:Cell Line; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D015539:Platelet Activation / Q000502:physiology; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins; D013917:Thrombin
chemical_list: D011971:Receptors, Immunologic; D011994:Recombinant Proteins; C473366:TREML1 protein, human; C471763:Treml1 protein, mouse; D013917:Thrombin