The Laminin 511/521 Binding Site on the Lutheran Blood Group Glycoprotein is Located at theFlexible Junction of Ig Domains 2 and 3

Mankelow, Tosti J. ; Burton, Nicholas ; Stedansdottir, Fanney O. ; Spring, Frances A. ; Parsons, Stephen F. ; Pesersen, Jan S. ; Oliveira, Cristiano L.P. ; Lammie, Donna ; Wess, Timothy ; Mohandas, Narla ; Chasis, Joel A. ; Brady, R. Leo ; Anstee, David J.

关键词: 59;    ANIMAL TISSUES;    BLOOD GROUPS;    CRYSTALLOGRAPHY;    DISEASE INCIDENCE;    ERYTHROCYTES;    FLEXIBILITY;    GLYCOPROTEINS;    MUTAGENESIS;    PLASMA;    RESIDUES;    SCATTERING;   

DOI  :  10.2172/945355
RP-ID  :  LBNL-1337E
PID  :  OSTI ID: 945355
Others  :  TRN: US200903%%204

美国|英语

来源: SciTech Connect

【 摘 要 】

The Lutheran blood group glycoprotein, first discovered on erythrocytes, is widely expressed in human tissues. It is a ligand for the {alpha}5 subunit of Laminin 511/521, an extracellular matrix protein. This interaction may contribute to vasocclusive 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.