The CEACAM1 N-terminal Ig domain mediates cis- and trans-binding and is essential for allosteric rearrangements of CEACAM1 microclusters.
Cell adhesion molecules (CAMs) sense the extracellular microenvironment and transmit signals to the intracellular compartment. In this investigation, we addressed the mechanism of signal generation by ectodomains of single-pass transmembrane homophilic CAMs. We analyzed the structure and homophilic interactions of carcinoembryonic antigen (CEA)-related CAM 1 (CEACAM1), which regulates cell proliferation, apoptosis, motility, morphogenesis, and microbial responses. Soluble and membrane-attached CEACAM1 ectodomains were investigated by surface plasmon resonance-based biosensor analysis, molecular electron tomography, and chemical cross-linking. The CEACAM1 ectodomain, which is composed of four glycosylated immunoglobulin-like (Ig) domains, is highly flexible and participates in both antiparallel (trans) and parallel (cis) homophilic binding. Membrane-attached CEACAM1 ectodomains form microclusters in which all four Ig domains participate. Trans-binding between the N-terminal Ig domains increases formation of CEACAM1 cis-dimers and changes CEACAM1 interactions within the microclusters. These data suggest that CEACAM1 transmembrane signaling is initiated by adhesion-regulated changes of cis-interactions that are transmitted to the inner phase of the plasma membrane.
Klaile
Esther
E
Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden.
Vorontsova
Olga
O
Sigmundsson
Kristmundur
K
Müller
Mario M
MM
Singer
Bernhard B
BB
Ofverstedt
Lars-Göran
LG
Svensson
Stina
S
Skoglund
Ulf
U
Obrink
Björn
B
D000494:Allosteric Regulation / Q000502:physiology; D000818:Animals; D015703:Antigens, CD / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D002448:Cell Adhesion / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000737:chemistry / Q000502:physiology; D004847:Epithelial Cells / Q000737:chemistry / Q000378:metabolism / Q000502:physiology; D006801:Humans; D051379:Mice; D010446:Peptide Fragments / Q000378:metabolism / Q000502:physiology*; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D051381:Rats; D011961:Receptors, Fc / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
D015703:Antigens, CD; C069847:CD66 antigens; D015815:Cell Adhesion Molecules; D010446:Peptide Fragments; D011961:Receptors, Fc