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Title: Diverse oligomeric states of CEACAM IgV domains

Journal Article · · Proceedings of the National Academy of Sciences of the United States of America
 [1]; ORCiD logo [1];  [1];  [2];  [3]
  1. Univ. of Maryland, Baltimore, MD (United States). School of Medicine. Inst. of Human Virology
  2. Univ. of Maryland, College Park, MD (United States). Dept. of Chemistry and Biochemistry
  3. Univ. of Maryland, Baltimore, MD (United States). School of Medicine. Inst. of Human Virology. Dept. of Medicine. Dept. of Microbiology and Immunology
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Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) comprise a large family of cell surface adhesion molecules that bind to themselves and other family members to carry out numerous cellular functions, including proliferation, signaling, differentiation, tumor suppression, and survival. They also play diverse and significant roles in immunity and infection. The formation of CEACAM oligomers is caused predominantly by interactions between their N-terminal IgV domains. Although X-ray crystal structures of CEACAM IgV domain homodimers have been described, how CEACAMs form heterodimers or remain monomers is poorly understood. To address this key aspect of CEACAM function, we determined in this paper the crystal structures of IgV domains that form a homodimeric CEACAM6 complex, monomeric CEACAM8, and a heterodimeric CEACAM6–CEACAM8 complex. To confirm and quantify these interactions in solution, we used analytical ultracentrifugation to measure the dimerization constants of CEACAM homodimers and isothermal titration calorimetry to determine the thermodynamic parameters and binding affinities of CEACAM heterodimers. We found the CEACAM6–CEACAM8 heterodimeric state to be substantially favored energetically relative to the CEACAM6 homodimer. Finally, our data provide a molecular basis for the adoption of the diverse oligomeric states known to exist for CEACAMs and suggest ways in which CEACAM6 and CEACAM8 regulate the biological functions of one another, as well as of additional CEACAMs with which they interact, both in cis and in trans.

Research Organization:
Univ. of Maryland, Baltimore, MD (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER); National Inst. of Health (NIH) (United States)
Contributing Organization:
Univ. of Maryland, College Park, MD (United States)
Grant/Contract Number:
AC02-06CH11357; AC02-76SF00515; S10RR15899; P41GM103393
OSTI ID:
1235483
Journal Information:
Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, Issue 44; ISSN 0027-8424
Publisher:
National Academy of Sciences, Washington, DC (United States)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 26 works
Citation information provided by
Web of Science

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Cited By (6)

The Roles of Carcinoembryonic Antigen in Liver Metastasis and Therapeutic Approaches journal January 2017
Carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) in Pancreatic Ductal Adenocarcinoma (PDA): An integrative analysis of a novel therapeutic target journal December 2019
Do available protein 3D structures reflect human genetic and functional diversity? journal May 2019
Co-expression of carcinoembryonic antigen-related cell adhesion molecule 6 and 8 inhibits proliferation and invasiveness of breast carcinoma cells journal June 2019
Helicobacter pylori adhesin HopQ disrupts trans dimerization in human CEACAM s journal June 2018
The Helicobacter pylori adhesin protein HopQ exploits the dimer interface of human CEACAMs to facilitate translocation of the oncoprotein CagA journal May 2018

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60 APPLIED LIFE SCIENCES
CEACAM
X-ray crystallography
isothermal titration calorimetry
analytical ultracentrifugation