The Laminin 511/521-binding site on the Lutheran blood group glycoprotein is located at the flexible junction of Ig domains 2 and 3.
The Lutheran blood group glycoprotein, first discovered on erythrocytes, is widely expressed in human tissues. It is a ligand for the alpha5 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.
Mankelow
Tosti J
TJ
Bristol Institute for Transfusion Sciences, National Blood Service, Southmead Road, Bristol, United Kingdom. tosti.mankelow@nbs.nhs.uk
Burton
Nicholas
N
Stefansdottir
Fanney O
FO
Spring
Frances A
FA
Parsons
Stephen F
SF
Pedersen
Jan S
JS
Oliveira
Cristiano L P
CL
Lammie
Donna
D
Wess
Timothy
T
Mohandas
Narla
N
Chasis
Joel Anne
JA
Brady
R Leo
RL
Anstee
David J
DJ
D001665:Binding Sites; D015815:Cell Adhesion Molecules / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D018360:Crystallography, X-Ray; D006023:Glycoproteins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007136:Immunoglobulins / Q000737:chemistry; D007797:Laminin / Q000378:metabolism*; D008188:Lutheran Blood-Group System; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009363:Neoplasm Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D053838:Scattering, Small Angle; D040681:Structural Homology, Protein
C090228:BCAM protein, human; D015815:Cell Adhesion Molecules; D006023:Glycoproteins; D007136:Immunoglobulins; D007797:Laminin; D008188:Lutheran Blood-Group System; D009363:Neoplasm Proteins