Crystal structure of Mycoplasma arthritidis mitogen complexed with HLA-DR1 reveals a novel superantigen fold and a dimerized superantigen-MHC complex.

Mycoplasma arthritidis -derived mitogen (MAM) is a superantigen that can activate large fractions of T cells bearing particular TCR Vβ elements. Here we report the crystal structure of MAM complexed with a major histocompatibility complex (MHC) antigen, HLA-DR1, loaded with haemagglutinin peptide 306-318 (HA). The structure reveals that MAM has a novel fold composed of two α-helical domains. This fold is entirely different from that of the pyrogenic superantigens, consisting of a β-grasped motif and a β barrel. In the complex, the N-terminal domain of MAM binds orthogonally to the MHC α1 domain and the bound HA peptide, and to a lesser extent to the MHC β1 domain. Two MAM molecules form an asymmetric dimer and cross-link two MHC antigens to form a plausible, dimerized MAM-MHC complex. These data provide the first crystallographic evidence that superantigens can dimerize MHC molecules. Based on our structure, a model of the TCR 2 MAM 2 MHC 2 complex is proposed.