title: Structural insight into the function of myelin basic protein as a ligand for integrin alpha M beta 2.
abstract: Multiple sclerosis (MS) is an inflammatory disease where phagocytic cells infiltrate the nerve tissue and act as terminal agents in destruction of the myelin sheath. However, the mechanism that triggers the ability of these cells to recognize myelin remains obscure. We show that myelin basic protein (MBP), a major autoantigen in MS, is a potent and specific ligand for the integrin alpha(M)beta(2) (Mac-1, CD11b/CD18) expressed mainly on phagocytic cells. MBP undergoes a dramatic conformational change when liberated from the lipid-rich environment of the myelin sheath. The MS drug glatiramer acetate mimics the conformationally labile regions of MBP, interacts in the unfolded state strongly with alpha(M)beta(2), and inhibits the MBP binding to alpha(M)beta(2). Our study reveals a link between MBP, glatiramer acetate, and the alpha(M)beta(2) integrin, and suggests a new model for MS pathogenesis based on the recognition of unfolded MBP by the alpha(M)beta(2) integrin.
authors.affiliation: Biophysical Immunology Laboratory, University of Aarhus, Aarhus, Denmark.
authors.forename: Romualdas
authors.initials: R
authors.lastname: Stapulionis
authors.forename: Cristiano Luis Pinto
authors.initials: CL
authors.lastname: Oliveira
authors.forename: Mikkel Carstensen
authors.initials: MC
authors.lastname: Gjelstrup
authors.forename: Jan Skov
authors.initials: JS
authors.lastname: Pedersen
authors.forename: Marianne Elisabet
authors.initials: ME
authors.lastname: Hokland
authors.forename: Søren Vrønning
authors.initials: SV
authors.lastname: Hoffmann
authors.forename: Knud
authors.initials: K
authors.lastname: Poulsen
authors.forename: Christian
authors.initials: C
authors.lastname: Jacobsen
authors.forename: Thomas
authors.initials: T
authors.lastname: Vorup-Jensen
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000737:chemistry / Q000378:metabolism / Q000502:physiology; D001667:Binding, Competitive / Q000276:immunology; D002417:Cattle; D002448:Cell Adhesion / Q000276:immunology; D000068717:Glatiramer Acetate; D006801:Humans; D020014:K562 Cells; D008024:Ligands; D016177:Macrophage-1 Antigen / Q000378:metabolism* / Q000502:physiology; D008863:Microspheres; D018716:Molecular Mimicry / Q000276:immunology; D009103:Multiple Sclerosis / Q000378:metabolism; D004676:Myelin Basic Protein / Q000737:chemistry* / Q000378:metabolism* / Q000502:physiology; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D017510:Protein Folding
chemical_list: D001324:Autoantigens; D008024:Ligands; D016177:Macrophage-1 Antigen; D004676:Myelin Basic Protein; D010455:Peptides; D000068717:Glatiramer Acetate