RRC ID 39137
Author Yamaguchi K, Kinosaki M, Goto M, Kobayashi F, Tsuda E, Morinaga T, Higashio K.
Title Characterization of structural domains of human osteoclastogenesis inhibitory factor.
Journal J Biol Chem
Abstract Osteoclastogenesis inhibitory factor (OCIF) is a heparin-binding secretory glycoprotein that belongs to the tumor necrosis factor receptor (TNFR) family. OCIF is present both as a approximately 60-kDa monomer and a disulfide-linked homodimer. We attempted to characterize the seven structural domains of OCIF by determining the capabilities of various OCIF mutants to inhibit osteoclastogenesis, to interact with heparin, and to form dimers. We also examined a potential of domains 5 and 6, death domain homologous regions (DDHs), for inducing cell death by expressing OCIF/Fas fusion proteins. Our results show that: (i) the N-terminal portion of OCIF containing domains 1-4, which have structural similarity to the extracellular domains of the TNFR family proteins, is sufficient to inhibit osteoclastogenesis; (ii) a heparin-binding site is located in domain 7, and affinity for heparin does not correlate with the inhibitory activity; (iii) Cys-400 in domain 7 is the residue responsible for dimer formation; and (iv) the C-terminal portion containing domains 5 and 6, DDHs, has a high potential for mediating a cytotoxic signal when it is expressed in cells as an OCIF/Fas fusion protein in which the transmembrane region of Fas is inserted in front of DDHs.
Volume 273(9)
Pages 5117-23
Published 1998-2-27
DOI 10.1074/jbc.273.9.5117
PII S0021-9258(17)47088-8
PMID 9478964
MeSH Apoptosis Cytotoxicity, Immunologic Dimerization Dose-Response Relationship, Drug Genetic Vectors Glycoproteins / genetics Glycoproteins / metabolism* Glycoproteins / pharmacology Growth Inhibitors / genetics Growth Inhibitors / metabolism* Growth Inhibitors / pharmacology Heparin / metabolism Humans Mutation Osteoclasts / drug effects* Osteoprotegerin Protein Binding Receptors, Cytoplasmic and Nuclear* Receptors, Tumor Necrosis Factor / genetics Receptors, Tumor Necrosis Factor / metabolism* Recombinant Fusion Proteins / pharmacology Signal Transduction Structure-Activity Relationship fas Receptor / genetics fas Receptor / pharmacology
IF 4.238
Times Cited 173
Human and Animal Cells ST2(RCB0224)