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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.
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 31 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
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| Copyright © 2007 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
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. 
