Solution structure of the CD3epsilondelta ectodomain and comparison with CD3epsilongamma as a basis for modeling T cell receptor topology and signaling.
Invariant CD3 subunit dimers (CD3epsilongamma, CD3epsilondelta, and CD3zetazeta) are the signaling components of the alphabeta T cell receptor (TCR). The recently solved structure of murine CD3epsilongamma revealed a unique side-to-side interface and central beta-sheets conjoined between the two C2-set Ig-like ectodomains, with the pairing of the parallel G strands implying a potential concerted piston-type movement for signal transduction. Although CD3gamma and CD3delta each dimerize with CD3epsilon, there are differential CD3 subunit requirements for receptor assembly and signaling among T lineage subpopulations, presumably mandated by structural differences. Here we present the solution structure of the heterodimeric CD3epsilondelta complex. Whereas the CD3epsilon subunit conformation is virtually identical to that in CD3epsilongamma, the CD3delta ectodomain adopts a C1-set Ig fold, with a narrower GFC front face beta-sheet that is more parallel to the ABED back face than those beta-sheets in CD3epsilon and CD3gamma. The dimer interface between CD3delta and CD3epsilon is highly conserved among species and of similar character to that in CD3epsilongamma. Glycosylation sites in CD3delta are arranged such that the glycans may point away from the membrane, consistent with a model of TCR assembly that allows the CD3delta chain to be in close contact with the TCR alpha-chain. This and many other structural and biological features provide a basis for modeling putative TCR/CD3 extracellular domain associations. The fact that the two clusters of transmembrane helices, namely, the three CD3epsilon-CD3gamma-TCRbeta segments and the five CD3epsilon-CD3delta-TCRalpha-CD3zeta-CD3zeta segments, are presumably centered beneath the G strand-paired CD3 heterodimers has important implications for TCR signaling.
Sun
Zhen-Yu J
ZY
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Kim
Sun Taek
ST
Kim
Il Chul
IC
Fahmy
Amr
A
Reinherz
Ellis L
EL
Wagner
Gerhard
G
D000595:Amino Acid Sequence; D000818:Animals; D017252:CD3 Complex / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D019281:Dimerization; D006031:Glycosylation; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D011487:Protein Conformation; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry* / Q000378:metabolism*; D015398:Signal Transduction; D012996:Solutions
D017252:CD3 Complex; D011948:Receptors, Antigen, T-Cell; D012996:Solutions