Structural basis of the dynamic human CEACAM1 monomer-dimer equilibrium

• Type of Material: Article
• Authors: Amit K. Gandhi, Harvard University; Zhen-Yu J. Sun, Dana Farber Cancer Institute; Walter M. Kim, Harvard University; Yu-Hwa Huang, Harvard University; Yasuyuki Kondo, Harvard University; Daniel A. Bonsor, University of Maryland; Eric Sundberg, Emory University; Gerhard Wagner, Harvard University; Vijay K. Kuchroo, Harvard University; Gregory A. Petsko, Harvard University; Richard S. Blumberg, Harvard University
• Language: English
• Date: 2021-03-19
• Publisher: Nature Research
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2021
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s42003-021-01871-2
• Title of Journal or Parent Work: Communications Biology
• Volume: 4
• Issue: 1
• Start Page: 360
• End Page: 360
• Grant/Funding Information: This work was supported by the NIH Grant 5R01DK051362-21 and the High Pointe Foundation to R.S.B., and 5P01AI073748-09 to V.K.K.
• Keywords: Science & Technology - Other Topics; Life Sciences & Biomedicine - Other Topics; Multidisciplinary Sciences; Science & Technology; Biology; Life Sciences & Biomedicine
• Research Categories: Biology, Microbiology; Chemistry, Biochemistry; Biology, Molecular; Biology, Virology

Abstract

Human (h) carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) function depends upon IgV-mediated homodimerization or heterodimerization with host ligands, including hCEACAM5, hTIM-3, PD-1, and a variety of microbial pathogens. However, there is little structural information available on how hCEACAM1 transitions between monomeric and dimeric states which in the latter case is critical for initiating hCEACAM1 activities. We therefore mutated residues within the hCEACAM1 IgV GFCC′ face including V39, I91, N97, and E99 and examined hCEACAM1 IgV monomer-homodimer exchange using differential scanning fluorimetry, multi-angle light scattering, X-ray crystallography and/or nuclear magnetic resonance. From these studies, we describe hCEACAM1 homodimeric, monomeric and transition states at atomic resolution and its conformational behavior in solution through NMR assignment of the wildtype (WT) hCEACAM1 IgV dimer and N97A mutant monomer. These studies reveal the flexibility of the GFCC’ face and its important role in governing the formation of hCEACAM1 dimers and selective heterodimers.