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J. Biol. Chem., Vol. 279, Issue 43, 44915-44923, October 22, 2004

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Quantifying the Effects of Molecular Orientation and Length on Two-dimensional Receptor-Ligand Binding Kinetics^*

Jun Huang, Juan Chen, Scott E. Chesla¶, Tadayuki Yago||, Padmaja Mehta||, Rodger P. McEver||**, Cheng Zhu¶, and Mian Long

From the National Microgravity Laboratory, Institute of Mechanics, Chinese Academy of Sciences, Beijing 100080, China, the ^¶Woodruff School of Mechanical Engineering and Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia 30332, and the ^||Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation and ^**Department of Biochemistry and Molecular Biology and Oklahoma Center for Medical Glycobiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104

Surface presentation of adhesion receptors influences cell adhesion, although the mechanisms underlying these effects are not well understood. We used a micropipette adhesion frequency assay to quantify how the molecular orientation and length of adhesion receptors on the cell membrane affected two-dimensional kinetic rates of interactions with surface ligands. Interactions of P-selectin, E-selectin, and CD16A with their respective ligands or antibody were used to demonstrate such effects. Randomizing the orientation of the adhesion receptor or lowering its ligand- and antibody-binding domain above the cell membrane lowered two-dimensional affinities of the molecular interactions by reducing the forward rates but not the reverse rates. In contrast, the soluble antibody bound with similar three-dimensional affinities to cell-bound P-selectin constructs regardless of their orientation and length. These results demonstrate that the orientation and length of an adhesion receptor influences its rate of encountering and binding a surface ligand but does not subsequently affect the stability of binding.

Received for publication, June 23, 2004 , and in revised form, August 3, 2004.

^* This work was supported by Natural Science Foundation of China Grants 10332060, 30225027, 10128205, and 10072071, Chinese Academy of Sciences Grant KJCX2-SW-L06, Ministry of Education grant TRAPOYT (to M. L.), and National Institutes of Health Grants AI 44902 and AI38282 (to C. Z.), TW 05774-01 (to C. Z. and M. L.), 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 may be addressed: George W. Woodruff School of Mechanical Engineering and Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332-0363. Tel.: 404-894-3269; Fax: 404-385-1397; E-mail: cheng.zhu{at}me.gatech.edu. To whom correspondence may be addressed: National Microgravity Laboratory, Institute of Mechanics, Chinese Academy of Sciences, Beijing 100080, P. R. China. Tel.: 86-10-6261-3540; Fax: 86-10-6261-3540; E-mail: mlong{at}imech.ac.cn.

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