title: Alteration of enzymatic properties of cell-surface antigen CD38 by agonistic anti-CD38 antibodies that prolong B cell survival and induce activation.
abstract: Leukocyte cell-surface antigen CD38 is a single-transmembrane protein. CD38 ligation by anti-CD38 antibodies triggers the growth or apoptosis of immune cells. Although the extracellular domain of CD38 has multifunctional catalytic activities including NAD(+) glycohydrolase and cyclase, the CD38-mediated cell survival or death appears to be independent of its catalytic activity. It is proposed that a conformational change of CD38 triggers the signalling. The conformational change of CD38 could influence its catalytic activity. However, the agonistic anti-CD38 antibody that alters the catalytic activity of CD38 has not been reported so far. In the present study, we demonstrated that two agonistic anti-mouse CD38 mAbs (CS/2 and clone 90) change the catalytic activities of CD38. CS/2 was clearly more potent than clone 90 in prolonging B cell survival and activation. CS/2 inhibited the NAD(+) glycohydrolase activity of both the isolated extracellular domain of CD38 (FLAG-CD38) and cell-surface CD38. Kinetic analysis suggested a non-competitive inhibition. On the other hand, clone 90 stimulated the NAD(+) glycohydrolase activity of FLAG-CD38 and had little effect on the NAD(+) glycohydrolase activity of cell-surface CD38. CS/2 and clone 90 had no effect on the cyclase activity of FLAG-CD38 and inhibited the cyclase activity of cell-surface CD38. Accordingly, these agonistic antibodies probably induce the conformational changes of CD38 that are evident in the distinct alterations of the catalytic site. The antibodies will be useful tools to analyze the conformational change of CD38 in the process of triggering B cell survival and the activation signal.
authors: Department of Hard Tissue Engineering, Biochemistry, Division of Bio-Matrix, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo 113-8549, Japan. m.yokoyama.bch@tmd.ac.jp
authors: Miki
authors: M
authors: Hara-Yokoyama
authors: Tomoko
authors: T
authors: Kimura
authors: Hiroaki
authors: H
authors: Kaku
authors: Motoaki
authors: M
authors: Wakiyama
authors: Yoko
authors: Y
authors: Kaitsu
authors: Mio
authors: M
authors: Inoue
authors: Seisuke
authors: S
authors: Kusano
authors: Mikako
authors: M
authors: Shirouzu
authors: Shigeyuki
authors: S
authors: Yokoyama
authors: Toshiaki
authors: T
authors: Katada
authors: Yoshio
authors: Y
authors: Hirabayashi
authors: Kiyoshi
authors: K
authors: Takatsu
authors: Masaki
authors: M
authors: Yanagishita
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000502:physiology*; D001402:B-Lymphocytes / Q000201:enzymology* / Q000276:immunology*; D002384:Catalysis; D002460:Cell Line; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D002999:Clone Cells; D004330:Drosophila / Q000166:cytology / Q000235:genetics; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D009244:NAD+ Nucleosidase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D015398:Signal Transduction / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D008024:Ligands; D009244:NAD+ Nucleosidase; D051997:ADP-ribosyl Cyclase 1