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J. Biol. Chem., Vol. 283, Issue 17, 11493-11500, April 25, 2008

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Replacing a Lectin Domain Residue in L-selectin Enhances Binding to P-selectin Glycoprotein Ligand-1 but Not to 6-Sulfo-sialyl Lewis x^*

Arkadiusz G. Klopocki¹, Tadayuki Yago¹, Padmaja Mehta¹, Jun Yang², Tao Wu, Anne Leppänen^¶3, Nicolai V. Bovin^||, Richard D. Cummings^¶4, Cheng Zhu^**, and Rodger P. McEver^¶5

From the Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, and ^¶Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, the Woodruff School of Mechanical Engineering and ^**Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia 30332, and the ^||Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya 16/10, 117997 Moscow, Russia

Selectin-ligand interactions (bonds) mediate leukocyte rolling on vascular surfaces. The molecular basis for differential ligand recognition by selectins is poorly understood. Here, we show that substituting one residue (A108H) in the lectin domain of L-selectin increased its force-free affinity for a glycosulfopeptide binding site (2-GSP-6) on P-selectin glycoprotein ligand-1 (PSGL-1) but not for a sulfated-glycan binding site (6-sulfo-sialyl Lewis x) on peripheral node addressin. The increased affinity of L-selectinA108H for 2-GSP-6 was due to a faster on-rate and to a slower off-rate that increased bond lifetimes in the absence of force. Rather than first prolonging (catching) and then shortening (slipping) bond lifetimes, increasing force monotonically shortened lifetimes of L-selectinA108H bonds with 2-GSP-6. When compared with microspheres bearing L-selectin, L-selectinA108H microspheres rolled more slowly and regularly on 2-GSP-6 at low flow rates. A reciprocal substitution in P-selectin (H108A) caused faster microsphere rolling on 2-GSP-6. These results distinguish molecular mechanisms for L-selectin to bind to PSGL-1 and peripheral node addressin and explain in part the shorter lifetimes of PSGL-1 bonds with L-selectin than P-selectin.

Received for publication, November 29, 2007 , and in revised form, January 14, 2008.

^* This work was supported by grants from the National Institutes of Health (to R. D. C., C. Z., and R. P. M.) and from the Molecular and Cell Biology Program of the Russian Academy of Sciences (to N. I. B). 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 These authors contributed equally to this work.

² Present address: Mechanical and Materials Engineering Department, University of Western Ontario, London, Ontario N6A 5B9, Canada.

³ Present address: Department of Biological and Environmental Sciences, Division of Biochemistry, University of Helsinki, 00790 Helsinki, Finland.

⁴ Present address: Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322.

⁵ To whom correspondence should be addressed: Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, 825 N.E. 13th St., Oklahoma City, OK 73104. Tel.: 405-271-6480; Fax: 405-271-3137; E-mail: rodger-mcever{at}omrf.org.

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