Abstract
The extracellular region of CD6 consists of three scavenger receptor cysteine-rich (SRCR) domains and binds activated leukocyte cell adhesion molecule (ALCAM), a member of the immunoglobulin superfamily (IgSF). Residues important for the CD6-ALCAM interaction have previously been identified by mutagenesis. A total of 22 CD6 residues were classified according to their importance for anti-CD6 monoclonal antibody (mAb) and/or ALCAM binding. The three-dimensional structure of the SRCR domain of Mac-2 binding protein has recently been determined, providing a structural prototype for the SRCR protein superfamily. This has made a thorough three-dimensional analysis of CD6 mutagenesis and mAb binding experiments possible. Mutation of buried residues compromised both mAb and ALCAM binding, consistent with the presence of structural perturbations. However, several residues whose mutation affected both mAb and ALCAM binding or, alternatively, only ligand binding were found to map to the surface in the same region of the domain. This suggests that the CD6 ligand binding site and epitopes of tested mAbs overlap and provides an explanation for the finding that these mAbs effectively block ALCAM binding. An approximate molecular model of CD6 was used to delineate the ALCAM binding site.
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Abbreviations
- ALCAM:
-
activated leukocyte cell adhesion molecule
- CD6D3:
-
third (membrane-proxi-mal) extracellular domain of CD6
- IgSF:
-
immunoglobulin superfamily
- mAb:
-
monoclonal antibody
- M2BP:
-
Mac-2 binding protein
- SRCR:
-
scavenger receptor cysteine-rich domain
- SRCRSF:
-
scavenger receptor cysteine-rich protein superfamily
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Bajorath, J. Three-Dimensional Analysis of CD6 Site-Directed Mutagenesis and Monoclonal Antibody Binding Studies Using the X-ray Structure of Mac-2 Binding Protein and a Molecular Model of the CD6 Ligand Binding Domain. J Mol Model 5, 263–270 (1999). https://doi.org/10.1007/s0089490050263
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DOI: https://doi.org/10.1007/s0089490050263