Human CEACAM1 N-domain dimerization is independent from glycan modifications

Dufrisne, Meagan Belcher; Swope, Nicole; Kieber, Marissa; Yang, Jeong‐Yeh; Han, Ji In; Li, Jason; Moremen, Kelley W.; Prestegard, James H.; Columbus, Linda

doi:10.1016/j.str.2022.02.003

Cited by 4 publications

(5 citation statements)

References 68 publications

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“…Further, B factor analysis of the hCEACAM1 oligomeric structure showed that the sites predicted to be associated with carbohydrate side-chain modifications (N70, N77, N81) as well as the amino acid residues along the ABED interface were characterized by high thermal motion and thus, flexibility. These results are further supported by a recent elegant study published at the time of this manuscript’s submission which directly demonstrates by NMR and structural (PDB code 7MU8) observations that dimer formation through hCEACAM1 GFCC’ face interactions is observed in the presence of partially glycosylated hCEACAM1 31 .…”

Section: Discussionsupporting

confidence: 81%

Structural analysis of human CEACAM1 oligomerization

et al. 2022

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The human (h) CEACAM1 GFCC’ face serves as a binding site for homophilic and heterophilic interactions with various microbial and host ligands. hCEACAM1 has also been observed to form oligomers and micro-clusters on the cell surface which are thought to regulate hCEACAM1-mediated signaling. However, the structural basis for hCEACAM1 higher-order oligomerization is currently unknown. To understand this, we report a hCEACAM1 IgV oligomer crystal structure which shows how GFCC’ face-mediated homodimerization enables highly flexible ABED face interactions to arise. Structural modeling and nuclear magnetic resonance (NMR) studies predict that such oligomerization is not impeded by the presence of carbohydrate side-chain modifications. In addition, using UV spectroscopy and NMR studies, we show that oligomerization is further facilitated by the presence of a conserved metal ion (Zn++ or Ni++) binding site on the G strand of the FG loop. Together these studies provide biophysical insights on how GFCC’ and ABED face interactions together with metal ion binding may facilitate hCEACAM1 oligomerization beyond dimerization.

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Section: Discussionsupporting

confidence: 81%

Structural analysis of human CEACAM1 oligomerization

et al. 2022

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“…The interplay between dynamics and function is further emphasized in many other studies that examine protein oligomerization, functional dynamics in enzymes, and ligand recognition. [7][8][9][10][11][12][13][14] Most often, this insight is obtained through NMR. 15 Despite the successes of NMR, measurement of dynamics can be difficult for large proteins and proteins exhibiting widespread microsecond-millisecond dynamics that broaden peaks.…”

Section: Introductionmentioning

confidence: 99%

“…The population of “on” and “off” states and the transitions between these states are described by the dynamics of the protein. The interplay between dynamics and function is further emphasized in many other studies that examine protein oligomerization, functional dynamics in enzymes, and ligand recognition 7–14 . Most often, this insight is obtained through NMR 15 .…”

Section: Introductionmentioning

confidence: 99%

Beyond structure: Deciphering site‐specific dynamics in proteins from double histidine‐based EPR measurements

et al. 2022

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Site-specific dynamics in proteins are at the heart of protein function. While electron paramagnetic resonance (EPR) has potential to measure dynamics in large protein complexes, the reliance on flexible nitroxide labels is limitating especially for the accurate measurement of site-specific β-sheet dynamics.Here, we employed EPR spectroscopy to measure site-specific dynamics across the surface of a protein, GB1. Through the use of the double Histidine (dHis) motif, which enables labeling with a Cu(II)nitrilotriacetic acid (NTA) complex, dynamics information was obtained for both α-helical and β-sheet sites. Spectral simulations of the resulting CW-EPR report unique site-specific fluctuations across the surface of GB1. Additionally, we performed molecular dynamics (MD) simulations to complement the EPR data. The dynamics observed from MD agree with the EPR results. Furthermore, we observe small changes in g k values for different sites, which may be due to small differences in coordination geometry and/or local electrostatics of the site. Taken together, this work expands the utility of Cu(II)NTA-based EPR measurements to probe information beyond distance constraints.

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“…CEACAM1 comprises an extracellular, a transmembrane and a cytoplasmatic domain (5,6). Due to alternative splicing 12 different variants exist in humans that differ in the composition of immunoglobulin (Ig)-like ectodomains as well as in the cytoplasmatic domain (7).…”

Section: Ceacam1 Structure and Signalingmentioning

confidence: 99%

The role of carcinoembryonic antigen-related cell adhesion molecule 1 in cancer

Götz,

Rueckschloss,

Balk

et al. 2023

Front. Immunol.

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The Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), also known as CD66a, is a member of the immunoglobulin superfamily. CEACAM1 was shown to be a prognostic marker in patients suffering from cancer. In this review, we summarize pre-clinical and clinical evidence linking CEACAM1 to tumorigenicity and cancer progression. Furthermore, we discuss potential CEACAM1-based mechanisms that may affect cancer biology.

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Human CEACAM1 N-domain dimerization is independent from glycan modifications

Cited by 4 publications

References 68 publications

Structural analysis of human CEACAM1 oligomerization

Structural analysis of human CEACAM1 oligomerization

Beyond structure: Deciphering site‐specific dynamics in proteins from double histidine‐based EPR measurements

The role of carcinoembryonic antigen-related cell adhesion molecule 1 in cancer

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