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Blood, 1 November 2007, Vol. 110, No. 9, pp. 3398-3406. Prepublished online as a Blood First Edition Paper on July 17, 2007; DOI 10.1182/blood-2007-06-094748. This Article Full Text Full Text (PDF) Supplemental Methods and Figures All Versions of this Article: blood-2007-06-094748v1 110/9/3398    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Mankelow, T. J. Articles by Anstee, D. J. Search for Related Content PubMed PubMed Citation Articles by Mankelow, T. J. Articles by Anstee, D. J. Related Collections Cell Adhesion and Motility Red Cells Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  RED CELLS The Laminin 511/521–binding site on the Lutheran blood group glycoprotein is located at the flexible junction of Ig domains 2 and 3 Tosti J. Mankelow1, Nicholas Burton2, Fanney O. Stefansdottir1, Frances A. Spring1, Stephen F. Parsons1, Jan S. Pedersen3, Cristiano L. P. Oliveira3, Donna Lammie4, Timothy Wess4, Narla Mohandas5, Joel Anne Chasis6, R. Leo Brady2, and David J. Anstee1 1 Bristol Institute for Transfusion Sciences (BITS), National Blood Service, Bristol, United Kingdom; 2 Department of Biochemistry, University of Bristol, Bristol, United Kingdom; 3 Department of Chemistry, University of Aarhus, Aarhus, Denmark; 4 School of Optometry and Vision Sciences, Cardiff University, Cardiff, United Kingdom; 5 New York Blood Center, New York City; and 6 University of California, Lawrence Berkeley National Laboratory, Berkeley The Lutheran blood group glycoprotein, first discovered on erythrocytes, is widely expressed in human tissues. It is a ligand for the 5 subunit of Laminin 511/521, an extracellular matrix protein. This interaction may contribute to vaso-occlusive events that are an important cause of morbidity in sickle cell disease. Using x-ray crystallography, small-angle x-ray scattering, and site-directed mutagenesis, we show that the extracellular region of Lutheran forms an extended structure with a distinctive bend between the second and third immunoglobulin-like domains. The linker between domains 2 and 3 appears to be flexible and is a critical determinant in maintaining an overall conformation for Lutheran that is capable of binding to Laminin. Mutagenesis studies indicate that Asp312 of Lutheran and the surrounding cluster of negatively charged residues in this linker region form the Laminin-binding site. Unusually, receptor binding is therefore not a function of the domains expected to be furthermost from the plasma membrane. These studies imply that structural flexibility of Lutheran may be essential for its interaction with Laminin and present a novel opportunity for the development of therapeutics for sickle cell disease. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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