The critical role of residues 43R and 44Q of carcinoembryonic antigen cell adhesion molecules-1 in the protection from killing by human NK cells.
The multifunctional carcinoembryonic Ag cell adhesion molecule (CEACAM)1 protein has recently become the focus of intense immunological research. We have previously shown that the CEACAM1 homophilic interactions inhibit the killing activity of NK cells. This novel inhibitory mechanism plays a key role in melanoma immune evasion, inhibition of decidual immune response, and controlling NK autoreactivity in TAP2-deficient patients. These roles are mediated mainly by homophilic interactions, which are mediated through the N-domain of the CEACAM1. The N-domain of the various members of the CEACAM family shares a high degree of similarity. However, it is still unclear which of the CEACAM family members is able to interact with CEACAM1 and what are the amino acid residues that control this interaction. In this study we demonstrate that CEACAM1 interacts with CEACAM5, but not with CEACAM6. Importantly, we provide the molecular basis for CEACAM1 recognition of various CEACAM family members. Sequence alignment reveals a dichotomy among the CEACAM family members: both CEACAM1 and CEACAM5 contain the R and Q residues in positions 43 and 44, respectively, whereas CEACAM3 and CEACAM6 contain the S and L residues, respectively. Mutational analysis revealed that both 43R and 44Q residues are necessary for CEACAM1 interactions. Implications for differential expression of CEACAM family members in tumors are discussed.
Markel
Gal
G
Lautenberg Center for General and Tumor Immunology, Hebrew University Hadassah Medical School, Jerusalem, Israel.
Gruda
Raizy
R
Achdout
Hagit
H
Katz
Gil
G
Nechama
Morris
M
Blumberg
Richard S
RS
Kammerer
Robert
R
Zimmermann
Wolfgang
W
Mandelboim
Ofer
O
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D001120:Arginine / Q000235:genetics; D002272:Carcinoembryonic Antigen; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D000939:Epitopes / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D058851:GPI-Linked Proteins; D005973:Glutamine / Q000235:genetics; D017261:Glycosylphosphatidylinositols / Q000378:metabolism; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D007930:Leucine / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D011485:Protein Binding / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D012694:Serine / Q000235:genetics
D015703:Antigens, CD; D000943:Antigens, Differentiation; D000951:Antigens, Neoplasm; C069847:CD66 antigens; C504117:CEACAM6 protein, human; D002272:Carcinoembryonic Antigen; C486183:Ceacam1 protein, mouse; D015815:Cell Adhesion Molecules; D000939:Epitopes; D058851:GPI-Linked Proteins; D017261:Glycosylphosphatidylinositols; D005973:Glutamine; D012694:Serine; D001120:Arginine; D007930:Leucine