title: A fibrillin-1-fragment containing the elastin-binding-protein GxxPG consensus sequence upregulates matrix metalloproteinase-1: biochemical and computational analysis.
abstract: Mutations in the gene for fibrillin-1 cause Marfan syndrome (MFS), a common hereditary disorder of connective tissue. Recent findings suggest that proteolysis, increased matrix metalloproteinase activity, and fragmentation of fibrillin-rich microfibrils in tissues of persons with MFS contribute to the complex pathogenesis of this disorder. In this study we show that a fibrillin-1 fragment containing a EGFEPG sequence that conforms to a putative GxxPG elastin-binding protein (EBP) consensus sequence upregulates the expression and production of matrix metalloproteinase (MMP)-1 by up to ninefold in a cell culture system. A mutation of the GxxPG consensus sequence site abrogated the effects. This is the first demonstration of such an effect for ligands other than elastin fragments. Molecular dynamics analysis of oligopeptides with the wildtype and mutant sequence support our biochemical results by predicting significant alterations of structural characteristics such as the potential for forming a type VIII beta-turn that are thought to be important for binding to the EBP. These results suggest that fibrillin-1 fragments may regulate MMP-1 expression, and that the dysregulation of MMPs related to fragmentation of fibrillin might contribute to the development of MFS. Our Gene Ontology (GO) analysis of the human proteome shows that proteins with multiple GxxPG motifs are highly enriched for GO terms related to the extracellular matrix. Matrix proteins with multiple GxxPG sites include fibrillin-1, -2, and -3, elastin, fibronectin, laminin, and several tenascins and collagens. Some of these proteins have been associated with disorders involving alterations in MMP regulation, and the results of the present study suggest a potential mechanism for these observations.
authors.affiliation: Institute of Medical Genetics, Charite University Hospital, Humboldt University, Augustenburger Platz, 13353 Berlin, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Booms
authors.forename: Andreas
authors.initials: A
authors.lastname: Ney
authors.forename: Frank
authors.initials: F
authors.lastname: Barthel
authors.forename: Gautier
authors.initials: G
authors.lastname: Moroy
authors.forename: Damian
authors.initials: D
authors.lastname: Counsell
authors.forename: Christoph
authors.initials: C
authors.lastname: Gille
authors.forename: Gao
authors.initials: G
authors.lastname: Guo
authors.forename: Reinhard
authors.initials: R
authors.lastname: Pregla
authors.forename: Stefan
authors.initials: S
authors.lastname: Mundlos
authors.forename: Alain J P
authors.initials: AJ
authors.lastname: Alix
authors.forename: Peter N
authors.initials: PN
authors.lastname: Robinson
mesh_terms: D000595:Amino Acid Sequence; D019295:Computational Biology; D016384:Consensus Sequence; D030562:Databases, Protein; D004790:Enzyme Induction / Q000502:physiology; D000071838:Fibrillin-1; D000071837:Fibrillins; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis* / Q000235:genetics; D008840:Microfilament Proteins / Q000235:genetics / Q000502:physiology*; D009154:Mutation; D010446:Peptide Fragments / Q000235:genetics / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation; D054392:Adipokines
chemical_list: D000071838:Fibrillin-1; D000071837:Fibrillins; D020781:Matrix Metalloproteinase 1; D008840:Microfilament Proteins; D010446:Peptide Fragments; D011956:Receptors, Cell Surface; C000605722:FBN1 protein, human; D054392:Adipokines; C054901:elastin-binding proteins