title: Cysteine-rich domain 1 of CD40 mediates receptor self-assembly.
abstract: The activation of CD40 on B cells, macrophages, and dendritic cells by its ligand CD154 (CD40L) is essential for the development of humoral and cellular immune responses. CD40L and other TNF superfamily ligands are noncovalent homotrimers, but the form under which CD40 exists in the absence of ligand remains to be elucidated. Here, we show that both cell surface-expressed and soluble CD40 self-assemble, most probably as noncovalent dimers. The cysteine-rich domain 1 (CRD1) of CD40 participated to dimerization and was also required for efficient receptor expression. Modelization of a CD40 dimer allowed the identification of lysine 29 in CRD1, whose mutation decreased CD40 self-interaction without affecting expression or response to ligand. When expressed alone, recombinant CD40-CRD1 bound CD40 with a K(D) of 0.6 μM. This molecule triggered expression of maturation markers on human dendritic cells and potentiated CD40L activity. These results suggest that CD40 self-assembly modulates signaling, possibly by maintaining the receptor in a quiescent state.
authors: Institut de Biologie Moléculaire et Cellulaire, Immunologie et Chimie Thérapeutiques, CNRS UPR 9021, 15 rue René Descartes, 67084 Strasbourg, France. cristianroberto.smulski@unil.ch
authors: Cristian R
authors: CR
authors: Smulski
authors: Julien
authors: J
authors: Beyrath
authors: Marion
authors: M
authors: Decossas
authors: Neila
authors: N
authors: Chekkat
authors: Philippe
authors: P
authors: Wolff
authors: Karine
authors: K
authors: Estieu-Gionnet
authors: Gilles
authors: G
authors: Guichard
authors: Daniel
authors: D
authors: Speiser
authors: Pascal
authors: P
authors: Schneider
authors: Sylvie
authors: S
authors: Fournel
mesh_terms: D019013:CD40 Antigens / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D023201:CD40 Ligand / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D055503:Protein Multimerization / Q000502:physiology*; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D019013:CD40 Antigens; D023201:CD40 Ligand