title: Predicted structure of MIF/CD74 and RTL1000/CD74 complexes.
abstract: Macrophage migration inhibitory factor (MIF) is a key cytokine in autoimmune and inflammatory diseases that attracts and then retains activated immune cells from the periphery to the tissues. MIF exists as a homotrimer and its effects are mediated through its primary receptor, CD74 (the class II invariant chain that exhibits a highly structured trimerization domain), present on class II expressing cells. Although a number of binding residues have been identified between MIF and CD74 trimers, their spatial orientation has not been established. Using a docking program in silico, we have modeled binding interactions between CD74 and MIF as well as CD74 and a competitive MIF inhibitor, RTL1000, a partial MHC class II construct that is currently in clinical trials for multiple sclerosis. These analyses revealed 3 binding sites on the MIF trimer that each were predicted to bind one CD74 trimer through interactions with two distinct 5 amino acid determinants. Surprisingly, predicted binding of one CD74 trimer to a single RTL1000 antagonist utilized the same two 5 residue determinants, providing strong suggestive evidence in support of the MIF binding regions on CD74. Taken together, our structural modeling predicts a new MIF(CD74)3 dodecamer that may provide the basis for increased MIF potency and the requirement for ~3-fold excess RTL1000 to achieve full antagonism.
authors: Neuroimmunology Research, VA Portland Health Care System, 3710 SW US Veterans Hosp. Rd, Portland, OR, 97239, USA.|Tykeson MS Research Laboratory, Department of Neurology UHS-46, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR, USA.
authors: Roberto
authors: R
authors: Meza-Romero
authors: Neuroimmunology Research, VA Portland Health Care System, 3710 SW US Veterans Hosp. Rd, Portland, OR, 97239, USA.|Tykeson MS Research Laboratory, Department of Neurology UHS-46, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR, USA.
authors: Gil
authors: G
authors: Benedek
authors: Department of Internal Medicine Yale University School of Medicine, 330 Cedar St, New Haven, CT, 06520, USA.
authors: Lin
authors: L
authors: Leng
authors: Department of Internal Medicine Yale University School of Medicine, 330 Cedar St, New Haven, CT, 06520, USA.
authors: Richard
authors: R
authors: Bucala
authors: Neuroimmunology Research, VA Portland Health Care System, 3710 SW US Veterans Hosp. Rd, Portland, OR, 97239, USA. vandenba@ohsu.edu.|Tykeson MS Research Laboratory, Department of Neurology UHS-46, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR, USA. vandenba@ohsu.edu.|Department of Molecular Microbiology & Immunology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR, USA. vandenba@ohsu.edu.
authors: Arthur A
authors: AA
authors: Vandenbark
mesh_terms: D000944:Antigens, Differentiation, B-Lymphocyte / Q000737:chemistry / Q000378:metabolism*; D002478:Cells, Cultured; D000949:Histocompatibility Antigens Class II / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000737:chemistry / Q000378:metabolism*; D008263:Macrophage Migration-Inhibitory Factors / Q000737:chemistry / Q000378:metabolism*; D009103:Multiple Sclerosis / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; D008263:Macrophage Migration-Inhibitory Factors; C542328:RTL1000 protein; D011993:Recombinant Fusion Proteins; C045084:invariant chain; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human
keywords: Binding residues; Inflammation; Molecular modeling; Protein interactions