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Review
. 2019 Apr:42:101296.
doi: 10.1016/j.smim.2019.101296.

CEACAM1 structure and function in immunity and its therapeutic implications

Walter M Kim  1 , Yu-Hwa Huang  1 , Amit Gandhi  1 , Richard S Blumberg  2
Affiliations
Review

CEACAM1 structure and function in immunity and its therapeutic implications

Walter M Kim et al. Semin Immunol. 2019 Apr.

Abstract

The type I membrane protein receptor carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) distinctively exhibits significant alternative splicing that allows for tunable functions upon homophilic binding. CEACAM1 is highly expressed in the tumor environment and is strictly regulated on lymphocytes such that its expression is restricted to activated cells where it is now recognized to function in tolerance pathways. CEACAM1 is also an important target for microbes which have co-opted these attributes of CEACAM1 for the purposes of invading the host and evading the immune system. These properties, among others, have focused attention on CEACAM1 as a unique target for immunotherapy in autoimmunity and cancer. This review examines recent structural information derived from the characterization of CEACAM1:CEACAM1 interactions and heterophilic modes of binding especially to microbes and how this relates to CEACAM1 function. Through this, we aim to provide insights into targeting CEACAM1 for therapeutic intervention.

Keywords: CEACAM1; Co-receptor; Immunity; Interaction.

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Figures

Figure 1.
Figure 1.. CEACAM1 structure, oligomerization, activation and targeted intervention.
A. Human and mouse CEACAM1 isoforms. The 12 unique human isoforms each contain the N-terminal IgV domain but due to alternative splicing, contain up to 3 IgC2 domains (A1,B,A2) and/or an Alu sequence, a transmembrane sequence and a short or long ITIM-containing cytoplasmic tail. The 4 mouse isoforms all contain the N-terminal IgV domain and either 3 or 1 IgC2 domain, a transmembrane domain and either a short or long ITIM-containing cytoplasmic tail. The homophilic and heterophilic binding surface on the IgV domain is denoted in red, glycosylation sites are depicted as brown circles and the ITIM tyrosines are denoted by black circles. B. hCEACAM1 IgV homodimer. One of the hCEACAM1 IgV binding partners is drawn in ribbon form (left) with residues involved in the hemophilic interaction surface drawn in stick model and labeled. The other hCEACAM1 binding partners is depicted in as a surface with the residues involved in hemophilic binding colored red. C. hCEACAM1 IgV homophilic interaction surface. The hCEACAM1 homophilic binding region on the GFCC’C” surface is denoted in red with surface representation of the interacting residues labeled. D. CEACAM1 oligomerization, activation and intervention. Left, CEACAM1 in monomeric and cis dimeric form on the membrane. Middle, trans engagement of the CEACAM1 IgV by homophilic GFCC’C”-mediated interactions (top) and heterophilic GFCC’C”-mediated microbial ligands interactions (bottom) induce CEACAM1 multimerization and activation of CEACAM1-mediated signaling pathways. Right, specific engagement of the CEACAM1 IgV GFCC’C” homophilic/heterophilic binding surface by an antibody disrupts the ability of CEACAM1 to participate in trans interactions and undergo multimerization thereby defusing CEACAM1-mediated signaling.
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