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Blood, 1 September 2001, Vol. 98, No. 5, pp. 1469-1479
IMMUNOBIOLOGY
Homophilic adhesion of human CEACAM1 involves N-terminal domain
interactions: structural analysis of the binding site
Suzanne M. Watt,
Ana M. Teixeira,
Guang-Qian Zhou,
Regis Doyonnas,
Youyi Zhang,
Fritz Grunert,
Richard S. Blumberg,
Motomu Kuroki,
Keith M. Skubitz, and
Paul A. Bates
From the Stem Cell Laboratory, National Blood Service,
Nuffield Department of Clinical and Laboratory Sciences, and the MRC
Molecular Haematology Unit, Institute of Molecular Medicine, Oxford,
United Kingdom; Faculdade de Ciencias do Desporto e Educacao Fisica da
Universidade de Coimbra, Coimbra, Portugal; GENOVAC AG, Freiburg,
Germany; Gastroenterology Division, Brigham and Women's Hospital,
Harvard Medical School, Boston, MA; First Department of Biochemistry,
School of Medicine, Fukuoka University, Fukuoka, Japan;
Hematology, Oncology and Transplantation, University of
Minnesota Medical School, Minneapolis, MN; Biomolecular Modelling
Laboratory, Imperial Cancer Research Fund, London, United Kingdom.
CEACAM1 on leukocytic, endothelial, and epithelial cells functions
in homophilic adhesion, tumor suppression, regulating cell adhesion and
proliferation, and in heterophilic adhesion as a receptor for
E-selectin and Neisseria meningiditis, Neisseria gonorrhoeae, Haemophilus influenzae, and murine coronaviruses. The 8 transmembrane isoforms of human CEACAM1 possess an extracellular N-terminal IgV domain, followed by variable numbers of IgC2 domains. To
establish which key amino acids contribute specifically to CEACAM1
homophilic adhesion, exposed amino acids in the N-terminal domain of a
soluble form of CEACAM1 were subjected to mutagenesis. Analyses of
mutant proteins with conformationally dependent antibodies indicated
that most mutations did not substantially affect the structural
integrity of CEACAM1. Nevertheless, decreased adhesion was observed for
the single mutants V39A or D40A (single-letter amino acid codes) in the
CC' loop and for the triple mutants located in the GFCC'C" face of the
N-terminal domain. Interestingly, whereas single mutations in R64 or
D82 that are predicted to form a salt bridge between the base of the D
and F  strands close to the critical V39 and D40 residues also
abolish adhesion, an amino acid swap (R64D and D82R), which maintains
the salt bridge was without significant effect. These studies indicate
that the CC' loop plays a crucial role in the homophilic adhesion
of CEACAM1. They further predict that specific hydrophobic amino acid
residues on the nonglycosylated GFCC'C" face of CEACAM1 N-terminal
domain are not only involved in heterophilic interactions with Opa
proteins and H influenzae, but are also critical for
protein-protein interactions between 2 CEACAM1 molecules on opposing cells.
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