Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA.
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
Commun Biol. 2022 Sep 30;5(1):1042. doi: 10.1038/s42003-022-03996-4.
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.
人（h）CEACAM1 GFCC' 面作为与各种微生物和宿主配体的同亲性和异亲性相互作用的结合位点。还观察到 hCEACAM1 在细胞表面形成寡聚体和微簇，据认为这些寡聚体和微簇调节 hCEACAM1 介导的信号转导。然而，hCEACAM1 更高阶寡聚化的结构基础目前尚不清楚。为了了解这一点，我们报告了 hCEACAM1 IgV 寡聚体晶体结构，该结构显示了 GFCC' 面介导的同源二聚化如何使高度灵活的 ABED 面相互作用得以产生。结构建模和核磁共振（NMR）研究预测，糖链侧链修饰的存在不会阻碍这种寡聚化。此外，我们通过紫外光谱和 NMR 研究表明，FG 环 G 链上保守的金属离子（Zn 或 Ni）结合位点的存在进一步促进了寡聚化。这些研究共同提供了关于 GFCC' 和 ABED 面相互作用以及金属离子结合如何促进 hCEACAM1 寡聚化超出二聚化的生物物理见解。
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