title: Fibulin 5 forms a compact dimer in physiological solutions.
abstract: Fibulin 5 is a 52-kDa calcium-binding epidermal growth factor (cbEGF)-rich extracellular matrix protein that is essential for the formation of elastic tissues. Missense mutations in fibulin 5 cause the elastin disorder cutis laxa and have been associated with age-related macular degeneration, a leading cause of blindness. We investigated the structure, hydrodynamics, and oligomerization of fibulin 5 using small angle x-ray scattering, EM, light scattering, circular dichroism, and sedimentation. Compact structures for the monomer were determined by small angle x-ray scattering and EM, and are supported by close agreement between the theoretical sedimentation of the structures and the experimental sedimentation of the monomer in solution. EM showed that monomers associate around a central cavity to form a dimer. Light scattering and equilibrium sedimentation demonstrated that the equilibrium between the monomer and the dimer is dependent upon NaCl and Ca2+ concentrations and that the dimer is dominant under physiological conditions. The dimerization of fragments containing just the cbEGF domains suggests that intermolecular interactions between cbEGFs cause dimerization of fibulin 5. It is possible that fibulin 5 functions as a dimer during elastinogenesis or that dimerization may provide a method for limiting interactions with binding partners such as tropoelastin.
authors.affiliation: Genetic Medicine, Manchester Academic Health Science Centre, Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9PL, United Kingdom.
authors.forename: Richard P O
authors.initials: RP
authors.lastname: Jones
authors.forename: Ming-Chuan
authors.initials: MC
authors.lastname: Wang
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Jowitt
authors.forename: Caroline
authors.initials: C
authors.lastname: Ridley
authors.forename: Kieran T
authors.initials: KT
authors.lastname: Mellody
authors.forename: Marjorie
authors.initials: M
authors.lastname: Howard
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Paul N
authors.initials: PN
authors.lastname: Bishop
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Lotery
authors.forename: Cay M
authors.initials: CM
authors.lastname: Kielty
authors.forename: Clair
authors.initials: C
authors.lastname: Baldock
authors.forename: Dorothy
authors.initials: D
authors.lastname: Trump
mesh_terms: D002118:Calcium / Q000737:chemistry / Q000378:metabolism; D002942:Circular Dichroism; D003483:Cutis Laxa / Q000235:genetics / Q000378:metabolism; D004547:Elastic Tissue / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D011485:Protein Binding / Q000502:physiology; D055503:Protein Multimerization / Q000502:physiology*; D020836:Protein Structure, Quaternary / Q000502:physiology; D012542:Scattering, Radiation; D012965:Sodium Chloride / Q000737:chemistry* / Q000378:metabolism; D014333:Tropoelastin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014965:X-Rays
chemical_list: D016326:Extracellular Matrix Proteins; C492373:FBLN5 protein, human; D014333:Tropoelastin; D012965:Sodium Chloride; D002118:Calcium