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J. Biol. Chem., Vol. 278, Issue 29, 26391-26400, July 18, 2003

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Model Glycosulfopeptides from P-selectin Glycoprotein Ligand-1 Require Tyrosine Sulfation and a Core 2-branched O-Glycan to Bind to L-selectin^*

Anne Leppänen , Tadayuki Yago , Vivianne I. Otto , Rodger P. McEver   and Richard D. Cummings  ¶

From the Department of Biochemistry and Molecular Biology, Oklahoma Center for Medical Glycobiology, University of Oklahoma Health Sciences Center and the Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104

L-selectin expressed on leukocytes is involved in lymphocyte homing to secondary lymphoid organs and leukocyte recruitment into inflamed tissue. L-selectin binds to the sulfated sialyl Lewis x (6-sulfo-sLe^x) epitope present on O-glycans of various glycoproteins in high endothelial venules. In addition, L-selectin interacts with the dimeric mucin P-selectin glycoprotein ligand-1 (PSGL-1) expressed on leukocytes. PSGL-1 lacks 6-sulfo-sLe^x but contains sulfated tyrosine residues (Tyr-SO₃)at positions 46, 48, and 51 and sLe^x in a core 2-based O-glycan (C2-O-sLe^x) on Thr at position 57. The role of tyrosine sulfation and core 2 O-glycans in binding of PSGL-1 to L-selectin is not well defined. Here, we show that L-selectin binds to a glycosulfopeptide (GSP-6) modeled after the extreme N terminus of human PSGL-1, containing three Tyr-SO₃ and a nearby Thr modified with C2-O-sLe^x. Leukocytes roll on immobilized GSP-6 in an L-selectin-dependent manner, and rolling is dependent on Tyr-SO₃ and C2-O-sLe^x on GSP-6. The dissociation constant for binding of L-selectin to GSP-6, as measured by equilibrium gel filtration, is 5 µM. Binding is dependent on Tyr-SO₃ residues as well as the sialic acid and fucose residues of C2-O-sLe^x. Binding to an isomeric glycosulfopeptide containing three Tyr-SO₃ residues and a core 1-based O-glycan expressing sLe^x was reduced by 90%. All three Tyr-SO₃ residues of GSP-6 are required for high affinity binding to L-selectin. Low affinity binding to mono- and disulfated GSPs is largely independent of the position of the Tyr-SO₃ residues, except for some binding preference for an isomer sulfated on both Tyr-48 and -51. These results demonstrate that L-selectin binds with high affinity to the N-terminal region of PSGL-1 through cooperative interactions with three sulfated tyrosine residues and an appropriately positioned C2-O-sLe^x O-glycan.

Received for publication, April 5, 2003 , and in revised form, May 2, 2003.

^* This work was supported by National Institutes of Health Grants AI48075 (to R. D. C.) and HL 65631 (to R. P. M.). 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 Oklahoma Health Sciences Center, 975 N.E. 10th St., BRC417, Oklahoma City, OK 73104. Tel.: 405-271-2481; Fax: 405-271-3910; E-mail: richard-cummings{at}ouhsc.edu.

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