Structural insight into the function of myelin basic protein as a ligand for integrin alpha M beta 2.
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.
Stapulionis
Romualdas
R
Biophysical Immunology Laboratory, University of Aarhus, Aarhus, Denmark.
Oliveira
Cristiano Luis Pinto
CL
Gjelstrup
Mikkel Carstensen
MC
Pedersen
Jan Skov
JS
Hokland
Marianne Elisabet
ME
Hoffmann
Søren Vrønning
SV
Poulsen
Knud
K
Jacobsen
Christian
C
Vorup-Jensen
Thomas
T
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
D001324:Autoantigens; D008024:Ligands; D016177:Macrophage-1 Antigen; D004676:Myelin Basic Protein; D010455:Peptides; D000068717:Glatiramer Acetate