title: Crystallographic and mutational analysis of the CD40-CD154 complex and its implications for receptor activation.
abstract: CD40 is a tumor necrosis factor receptor (TNFR) family protein that plays an important role in B cell development. CD154/CD40L is the physiological ligand of CD40. We have determined the crystal structure of the CD40-CD154 complex at 3.5 Å resolution. The binding site of CD40 is located in a crevice formed between two CD154 subunits. Charge complementarity plays a critical role in the CD40-CD154 interaction. Some of the missense mutations found in hereditary hyper-IgM syndrome can be mapped to the CD40-CD154 interface. The CD40 interaction area of one of the CD154 subunits is twice as large as that of the other subunit forming the binding crevice. This is because cysteine-rich domain 3 (CRD3) of CD40 has a disulfide bridge in an unusual position that alters the direction of the ladder-like structure of CD40. The Ser(132) loop of CD154 is not involved in CD40 binding but its substitution significantly reduces p38- and ERK-dependent signaling by CD40, whereas JNK-dependent signaling is not affected. These findings suggest that ligand-induced di- or trimerization is necessary but not sufficient for complete activation of CD40.
authors.affiliation: Department of Biology, College of Bioscience & Biotechnology, Chungnam National University, Daejon, Korea.
authors.forename: Hyun-Jung
authors.initials: HJ
authors.lastname: An
authors.forename: Young Jin
authors.initials: YJ
authors.lastname: Kim
authors.forename: Dong Hyun
authors.initials: DH
authors.lastname: Song
authors.forename: Beom Suk
authors.initials: BS
authors.lastname: Park
authors.forename: Ho Min
authors.initials: HM
authors.lastname: Kim
authors.forename: Ju Dong
authors.initials: JD
authors.lastname: Lee
authors.forename: Sang-Gi
authors.initials: SG
authors.lastname: Paik
authors.forename: Jie-Oh
authors.initials: JO
authors.lastname: Lee
authors.forename: Hayyoung
authors.initials: H
authors.lastname: Lee
mesh_terms: D000818:Animals; D001665:Binding Sites; D019013:CD40 Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D023201:CD40 Ligand / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018360:Crystallography, X-Ray; D004220:Disulfides; D057809:HEK293 Cells; D006801:Humans; D053306:Hyper-IgM Immunodeficiency Syndrome / Q000235:genetics / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000502:physiology*; D013329:Structure-Activity Relationship
chemical_list: D019013:CD40 Antigens; D004220:Disulfides; D023201:CD40 Ligand; D048670:MAP Kinase Kinase 4