title: Molecular analysis of fibulin-5 function during de novo synthesis of elastic fibers.
abstract: Elastic fibers contribute to the structural support of tissues and to the regulation of cellular behavior. Mice deficient for the fibulin-5 gene (fbln5(-/-)) were used to further elucidate the molecular mechanism of elastic fiber assembly. Major elastic fiber components were present in the skin of fbln5(-/-) mice despite a dramatic reduction of mature elastic fibers. We found that fibulin-5 preferentially bound the monomeric form of elastin through N-terminal and C-terminal elastin-binding regions and to a preexisting matrix scaffold through calcium-binding epidermal growth factor (EGF)-like (CB-EGF) domains. We further showed that adenovirus-mediated gene transfer of fbln5 was sufficient to regenerate elastic fibers and increase elastic fiber-cell connections in vivo. A mutant fibulin-5 lacking the first 28 amino acids of the first CB-EGF domain, however, was unable to rescue elastic fiber defects. Fibulin-5 thus serves as an adaptor molecule between monomeric elastin and the matrix scaffold to aid in elastic fiber assembly. These results also support the potential use of fibulin-5 as a therapeutic agent for the treatment of elastinopathies.
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9148, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zheng
authors.forename: Elaine C
authors.initials: EC
authors.lastname: Davis
authors.forename: James A
authors.initials: JA
authors.lastname: Richardson
authors.forename: Barry C
authors.initials: BC
authors.lastname: Starcher
authors.forename: Tiansen
authors.initials: T
authors.lastname: Li
authors.forename: Robert D
authors.initials: RD
authors.lastname: Gerard
authors.forename: Hiromi
authors.initials: H
authors.lastname: Yanagisawa
mesh_terms: D000256:Adenoviridae; D000818:Animals; D000831:Animals, Newborn; D016466:CHO Cells; D019556:COS Cells; D002522:Chlorocebus aethiops; D019902:Chondrocytes / Q000166:cytology; D006224:Cricetinae; D003412:Cricetulus; D020405:Dermis / Q000166:cytology; D004547:Elastic Tissue / Q000166:cytology* / Q000378:metabolism*; D004548:Elasticity; D004549:Elastin / Q000235:genetics; D004815:Epidermal Growth Factor / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000737:chemistry / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology; D018014:Gene Transfer Techniques; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism*; D012995:Solubility
chemical_list: D016326:Extracellular Matrix Proteins; C120769:Fbln5 protein, mouse; C492372:Fbln5 protein, rat; D011994:Recombinant Proteins; D004815:Epidermal Growth Factor; D004549:Elastin